Kras g12v targeted therapy. Sep 6, 2023 · Drilon, Alexander, et al.

Kras g12v targeted therapy 9 vs. Targeted therapy usually has a profound immunomodulatory effect on the TME, so targeted therapy combined with immunotherapy should be a strong combinational therapeutic strategy 201,202. 244 found that lipoplexes of si-FOSL-1 and si-YAP reduce the tumor growth in mice carrying tumors induced by Apr 8, 2024 · –Data support ongoing IND-enabling studies for planned clinical evaluation in KRAS G12V-driven the resistance paradigms of targeted therapy in oncology. In other ways, sequential administration of cell-cycle kinases CDK4 and CDK6 inhibitors after taxane treatment reduced cell proliferation in PDAC mouse model with both KRAS G12V and Cdkn2a-null mutations. Most cases display an aggressive clinical behavior, but knowledge about treatment approaches is limited, especially for targeting KRAS. However, drugs specifically targeting KRAS G12V are not yet available. In addition to markedly reversing the status quo of reliance on radiotherapy, chemotherapy, and surgery, these drugs have radically transformed Jan 16, 2023 · Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. 2-fold reduction in tumor volume was achieved by the knockdown of G12V mutant by highly specific KRAS G12V single-guide RNA (sgRNA) in a xenograft model without altering the Feb 13, 2024 · KRAS mutations in plasma ctDNA and genomic DNA from tumor tissues were detected using ddPCR on a QX200 Droplet Digital PCR System (Bio‐Rad Laboratories) with a ddPCR™ KRAS G12/G13 Screening Kit (Bio‐Rad Laboratories), which covers seven common KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D). That started to change in May 2021, when the Food and Drug Administration granted accelerated approval to sotorasib (Lumakras®) for lung cancers caused by a particular KRAS mutation, called KRAS G12C. , a clinical stage biopharmaceutical company focused on the development of precision immunotherapies for treatment of patients with solid tumors, today announced that a Trial-In-Progress poster for the Company’s Phase 1 clinical trial evaluating AFNT-211 targeting KRAS G12V will Background The targeting of mutated neoantigens with T-cell receptor (TCR) based therapies represents a promising strategy to treat cancer. Apr 8, 2024 · RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. 4 months, respectively; p = 0. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations [1]. (2018) reported that the expression of PD-L1 is significantly correlated with KRAS gene Dec 13, 2024 · Targeted KRASG12V degradation elicits efficient and durable lung adenocarcinoma regression in vivo Alberto Martín 1,# , Inés M. We showed the course of the disease as well as systematic imaging manifestations of lung cancer with osteoblastic bone reaction and discussed their mechanisms. 046). May 13, 2024 · There are currently numerous small-molecule inhibitors, PROTACs, TCRs, and vaccines targeting KRAS G12D and G12V. Sep 30, 2024 · 3. This review aims to comprehensively examine the . The KRAS Nov 14, 2022 · Purpose For the first-line treatment of KRAS mutant non-small cell lung cancer (NSCLC) patients, immunotherapy or platinum-based chemotherapy are the main treatment method. Lopez-Chavez, A. Nov 14, 2024 · However, The first-line clinical treatment regimen for KRAS-mutant NSCLC patients remains similar to that for patients without driver genes, primarily involving immunotherapy combined with chemotherapy, where bevacizumab plays a significant role. The KRAS G12D mutation subtype is present in more than 40% of pancreatic ductal adenocarcinoma (PDAC). Further, Afatinib, an approved pan-ERBB inhibitor, was shown to reduce View Clinical Trials for KRAS G12A KRAS G12A serves as an inclusion eligibility criterion in 1 clinical trial, of which 1 is open and 0 are closed. In recent years, preliminary results from early clinical trials show that direct inhibition of KRAS G12C has become possible, which may provide a novel targeted treatment for a number of patients with advanced CRC . Jun 24, 2024 · Here, we report that KRAS G12V is a good neoantigen candidate for people with the HLA-A*11:01 type, and combined therapy with a single neoantigen mRNA vaccine targeting KRAS G12V and the Nov 15, 2021 · Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have Apr 18, 2024 · The first clinically available KRAS G12C inhibitors, sotorasib and adagrasib, have demonstrated promising clinical efficacy across multiple solid tumors and represent the first approved Collectively, our data suggest that TCR-engineered CD4 + T cells can be used to target KRAS G12V mutation presented by HLA-DPB1*03:01 and DPB1*14:01, which provide a high population coverage and are more suitable for the clinical transformation for Chinese, and mediate tumor killing effect like CD8 + T cells. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived Jun 28, 2024 · Considering that KRAS mutation is believed to be a potent driver of resistance to immunotherapy and targeted therapy, we further evaluated the role of TKD in sensitizing cancers to programmed cell KRAS signaling pathways and impact on the TME, stroma and metabolism with strategies to target RAS. KRAS G12C (OFF) Inhibitors. Dec 2, 2024 · Amongst these, KRAS is the most frequently mutated of the RAS isoforms, with a remarkably high mutational prevalence in gastrointestinal (GI) malignancies, including 90% of pancreatic ductal adenocarcinomas (PDAC) and 50% of colorectal cancers (CRC). Introduction Targeted Therapy Target Mechanism Description; KRAS Inhibitors: KRAS Mutations: KRAS inhibitors target the KRAS protein, which is involved in cell signaling pathways that control cell growth and division. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. There are no active clinical trials specifically targeting KRAS G12V, KRAS G13, and KRAS Q61 mutations. Oct 12, 2023 · KRAS mutations are broadly recognized as promising targets for tumor therapy. Sep 24, 2019 · We observed changes in RasGTP levels and in ERK phosphorylation with cetuximab treatment for KRAS WT CaCo2 cells, but not in the CRC cells with a KRAS G12D mutation, a KRAS G12V mutation, or a KRAS G13D mutation with a co-occurring NF1 mutation . Jan 1, 2025 · Several studies have shown that different KRAS subtypes may impart variable therapeutic responsiveness 3 and survival. May 13, 2024 · developed targeting KRAS G12V16,17 and KRAS G12D. Sep 5, 2023 · Purpose Mesonephric-like adenocarcinomas (MLA) of the female genital tract represent a rare and relatively recently described neoplasm exhibiting characteristic morphologic and immunohistochemical findings commonly associated with a KRAS-mutation. After 24 h of stabilization, cells were incubated with 0 to 1000 μM of Olaparib (MedChemExpress, HY-10162), Gefitinib (MedChemExpress, HY-50895), Erlotinib (MedChemExpress, HY Dec 8, 2016 · HLA-A*11:01–restricted KRAS G12D and KRAS G12V–reactive T-cell receptors have been isolated from immunized HLA-A*11:01 transgenic mice, 23 although these receptors have not yet been evaluated Early anti-KRAS siRNAs such as AZD-4785 targeted all KRAS isoforms; however, the trial for AZD-4785 was discontinued . While this cancer has shown remarkable therapy resistance, new approaches to inhibit mutated KRAS, KRAS activators and effectors show promise in breaking this therapeutic There is a growing unmet need for a personalized therapy approach for patients with KRAS-mutant colorectal cancer. Moreover, multiple pan-KRAS and pan-RAS inhibitors are in clinical trials with promising efficacy. The KRAS gene normally serves as an information For PDAC patients, however, a mutation that replaces Glycine at codon 12 with Aspartic Acid (G12D) is the most common mutational event in KRAS, representing approximately 45% of KRAS mutations, as previously mentioned , and only a very modest proportion of patients would benefit from G12C targeted therapy. Targeted therapy is typically reserved as a second-line treatment. One of the most exciting drug development areas against colorectal cancer is the targeting of undruggable kinases and kinase-substrate molecules, although whether and how they can be integrated Jan 9, 2022 · 3. Feb 12, 2021 · Though KRAS genetic mutations have long been considered impossible to treat with drugs, MD Anderson researchers are making breakthroughs in developing targeted therapies to treat these mutations, which are frequent drivers in lung, colorectal and pancreatic cancers. 8%) [21,27]—the number of KRAS G12V-mutated samples in our population of study at La Paz University Hospital was very low (13 out of 554 total Sep 26, 2024 · It is called KRAS because it was first identified as causing cancer in Kirsten rat sarcoma virus. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. KRAS-mutations may alter responses to standard treatment regi-mens. Nov 18, 2023 · Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. Evidence in preclinical and clinical settings has proved excellent efficacy of several inhibitors in KRAS mutant CRC. Our research offers a paradigm shift in the pursuit of effective KRAS-targeted interventions, representing a significant step towards personalized and impactful cancer therapeutics. 5 KRAS codon 13 Nov 6, 2021 · Despite the effort, KRAS is still considered ‘undruggable’, and treatment of KRAS-mutant CRC remains a challenge. Lan et al. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including May 11, 2024 · The 2023 NCCN guidelines for the first time recommended KRASG12C targeted drug Adagrasib for the treatment of KRASG12C mutant NSCLC, which is a significant breakthrough for KRAS treatment targets Dec 1, 2021 · Most KRAS mutations are missense mutations of the 12th codon, glycine. KRAS is the most frequently mutated oncogene in human cancer. Two KRAS inhibitors, sotorasib and adagrasib, have recently been approved for the treatment of patients with advanced non-small cell lung cancer with the KRAS G12C mutation, while studies on their efficacy are still ongoing. Nat. O’Reilly says. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity Jan 12, 2023 · MRTX1133 is the first KRAS-blocking drug, and the first targeted therapy of any kind, to have such promising results in these mouse models of pancreatic cancer, said Ji Luo, Ph. KRAS is located on the short arm of chromosome 12 and is a member of the RAS oncogene family along with 2 other isoforms, neuroblastoma rat sarcoma viral oncogene (NRAS) and Harvey rat sarcoma viral oncogene (HRAS) (chromosomes 1 and 11 respectively) (). On May 28, 2021, the first KRAS G12C targeted therapy was approved (Sotorasib), opening up another line of therapy for 1 in 8 non-small cell lung cancer patients who are impacted by this biomarker. Jun 25, 2021 · G12C is one of several KRAS mutations found in cancer cells. 8, 9, 10 Despite many attempts, developing therapeutics targeting KRAS remains challenging. Oct 31, 2023 · Although in recent years FDA approval of two KRAS G12C inhibitors (sotorasib/Lumakras and adagrasib/Krazati) made oral targeted therapies a viable treatment option for those cancers, the effectiveness of the drugs has been limited, according to Edwin Yau, MD, PhD, Assistant Professor of Oncology in the departments of Medicine and Cancer 3 days ago · Quanta Therapeutics announced advancements in its KRAS-directed drug candidates, including FDA IND clearance for QTX3544, a G12V-preferring multi-KRAS inhibitor, allowing for a Phase 1 clinical trial. Keywords: KRAS mutation, Lung cancer, Targeted therapy, Predictive factor, Prognostic factor. However, clinical studies on covalent KRAS G12C inhibitors have rapidly confronted resistance in patients. We selected two CRC cell lines, SW620 and SW480, containing the KRAS c. 4 In the BATTLE trial which randomized patients to various targeted therapies, KRAS G12C and G12V were associated with shorter progression-free survival compared with other KRAS subtypes or wild-type KRAS. T cell receptors (TCRs) can specifically recognize KRAS mutant neoantigens presented by human lymphocyte antigen (HLA View Clinical Trials for KRAS G12V KRAS G12V serves as an inclusion eligibility criterion in 6 clinical trials, of which 5 are open and 1 is closed. 9% ORR and 14. Moreover, a recent study revealed that the KRASG12V mutation in NSCLC can upregulate programmed death ligand Jan 11, 2022 · Kim et al. A Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors. Nov 25, 2023 · Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Aug 31, 2021 · Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. 18 In pan-creatic cancer, there is a case report of tumor regression after therapy with KRAS G12D–specificTCRs. "SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy. 4. Novel KRAS (G12C) inhibitors induce a shift of the TME from immunosuppressive to immunoreactive. found that ERBB signaling was activated in human KRAS-mutated lung adenocarcinoma. , 7 various subtypes of mutations, G12VKRAS mutations are pre-dominant in smokers [8]. 35 versus Jan 19, 2021 · An analysis of 43 KRAS mutant NSCLC patients who were enrolled in the BATTLE-1 (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial determined that KRAS mutation variants G12C and G12V were significantly associated with worse median PFS compared to other KRAS variants or wild-type KRAS (1. 2 %), colorectal (8. 2 KRAS G12V mutation treatment strategies. Mar 2, 2023 · Investigators will recruit patients with metastatic cancer whose tumors carry a KRAS G12V or G12D mutation to receive the SLATE-KRAS vaccine as well as the KRAS-targeted TCR T-cell therapy. After stimulation with mutated KRAS G12D and KRAS G12V in vitro, CD4 + and CD8 + memory T cells were identified in 3 of 6 metastatic cancer [ 103 ]. Moll HP et al. In addition, patients with KRAS G12V-positive lung cancer have a poor OS and a high recurrence rate. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS Dec 3, 2023 · For example, high affinities of TCRs against KRAS G12D and KRAS G12V variants have successfully been studied [101, 102]. Because mKRAS is an intracellular membrane localized protein and not Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. Several new strategies, such as covalently targeting mutant KRAS, inhibiting KRAS interaction with associated proteins required for membrane association, inhibiting KRAS-driven malignant phenotypes and KRAS synthetic lethal interactions, have showed some promise in cancer therapy and may open new window for KRAS targeted anticancer drugs4. Nonetheless, since KRAS was found to Dec 9, 2024 · Medigene AG Sets KRAS G12V as Initial Target for Revolutionary Cancer Therapy. Patients with KRAS G12V mutations were less sensitive to chemotherapy and had worse PFS than non-KRAS G12V mutated patients (median PFS (mPFS), 2. Cell-based therapies, such as CAR T-cell, tumor infiltrating lymphocytes, and TCR T-cell therapies like the one developed by Rosenberg, have yet to come to Sep 6, 2023 · Drilon, Alexander, et al. Jan 19, 2021 · An analysis of 43 KRAS mutant NSCLC patients who were enrolled in the BATTLE-1 (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial determined that KRAS mutation variants G12C and G12V were significantly associated with worse median PFS compared to other KRAS variants or wild-type KRAS (1. Combine and conquer: challenges for targeted therapy combinations in early phase trials. KRAS mutations, particularly G12C, G12D, G12V, and G12R Apr 4, 2024 · “A KRAS inhibitor was considered the holy grail of oncology, but the tumors are finding ways around it. KRas G12C and G12V had increased signaling through Ral and decreased Dec 6, 2023 · Targeted therapy has fundamentally altered the diagnosis and treatment of clinical cancers. Adagrasib is the first KRAS-targeting drug to be approved for colorectal cancer. García-Pérez 2,# , Sonia San José 1 , Pep Rojo 2 , Carlos Riego-Mejías 2 , Cristina Dec 4, 2023 · In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRASG12C covalent inhibitors in other KRASG12C-positive malignancies, novel KRAS of 43 KRAS mutant NSCLC patients who were enrolled in the BATTLE-1 (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial determined that KRAS mutation variants G12C and G12V were significantly associated with worse median PFS compared to other KRAS variants or wild-type KRAS (1. investigated the Nov 9, 2024 · Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. Many methods are being assessed to overcome this resistance, along with various Abstract. KRAS G13D mutation tended to be the only prognostic marker for stages I–III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy. Jan 4, 2024 · KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. 9, 10, 11 In addition, many studies have explored the indirectly targeted therapy of upstream and downstream KRAS pathways, and recently, there has been a breakthrough in the directly targeted therapy of KRAS. Medigene AG (FSE: MDG1), an innovative company specializing in oncology, has recently made a significant stride in its mission to develop advanced T cell receptor (TCR)-guided therapies tailored for cancer treatment. Proof of concept for this approach recently was demonstrated in a patient with metastatic pancreatic cancer who experienced a clinical response after infusion of T cells engineered to express TCRs targeting KRAS G12D neoepitopes. 1. By inhibiting KRAS, these drugs aim to interrupt the proliferation of cancer cells. Aug 1, 2024 · Clinicians are also exploring autologous T cell therapy for patients with KRAS G12D mutations (NCT06218914), using modified T-cell receptors (NCT03745326), using a KRAS-targeted vaccine (NCT05254184). Dec 12, 2023 · KRAS mutations have been described as one of the founder carcinogenic mutation in the genome in more than 80% of pancreatic ductal adenocarcinomas (PDACs) and more than 30% of colorectal cancer (CRC), biliary tract cancers and lung adenocarcinomas , prompting the interest in identifying specific anti-KRAS targeted therapies for cancer treatment Patients with KRAS mutations, however, lacked specific targeted therapy until the recent FDA approval of sotorasib, a specific inhibitor of KRAS G12C mutant protein. May 28, 2021 · This is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers. 1, 2, 3 Because of the vital clinical significance of KRAS, the National Comprehensive Cancer Network (NCCN) highly recommends that patients with CRC be tested for the Nov 6, 2024 · The team will present three additional posters with preclinical data from its non-viral TRAC-knocked-in T cell therapy targeting TP53-R175H and bi-specific T cell engager programs targeting TP53 Jun 21, 2024 · The US Food and Drug Administration has granted accelerated approval for the targeted therapy adagrasib (Krazati ®) in combination with the drug cetuximab (Erbitux ®) for people with advanced colorectal cancer caused by a gene mutation called KRAS-G12C. Here, we report a high-throu … Dec 9, 2024 · MDG3010 is the first TCR-TCE therapy program in Medigene´s pipeline and is specifically designed to target the neoantigen KRAS (Kirsten rat sarcoma viral oncogene homologue) G12V, selected from one of the TCR candidates within Medigene’s KRAS-targeting TCR library. May 15, 2024 · Abstract. A limitation of our case was that we could not perform molecular analysis by Dec 27, 2024 · KRAS G12V mutations have been reported in pancreatic (28. Oct 30, 2024 · PURPOSEThis phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant Onvansertib ± SoC shows 76. These mutations result in changes from glycine to another amino acid in the KRAS protein. The success of drugs targeting KRAS^G12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. As mentioned, the G12R mutation also occurs at high frequency in PDAC (17% of all KRAS mutations). Jan 28, 2024 · In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. Pancreatic cancer is mainly driven by mutations in the KRAS oncogene. 1 However, TCR therapy is Jan 30, 2018 · 1. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. ” When it is on, the protein sends signals that tell the cell to grow and divide. Jan 4, 2022 · In this study, a shorter and statistically significant PFS was observed when the G12V mutant was compared with WT patients (2. Despite the recognized significance of the KRAS gene in cancer, the discovery of KRAS inhibitors has proven to be exceedingly challenging, rendering KRAS once deemed ‘undruggable’ due to the smooth surface lacking discernible binding sites, the spatial structure lacking deep hydrophobic pocket and hindering the identification of high-affinity Feb 21, 2024 · In this episode of Targeted Talks, Aaron Lisberg, MD, discusses results from the phase 3 TROPION-Lung01 study of datopotamab in advanced or metastatic non–small cell lung cancer. To r … May 9, 2024 · Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. The development history of KRAS inhibitors. 35 G > T (G12V) mutant allele (Supplementary Table 1). A phase I/II clinical trial is currently active, utilizing G12V-specific T-cell therapy for advanced pancreatic cancer (NCT04146298). Introduction In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. With the development of targeted therapy, mutations in KRAS have become key indicators for the effectiveness of EGFR monoclonal antibody‐targeted therapy and acquired drug resistance in colorectal cancer (CRC). 7 Several attempts have been made to overcome the most common and aggressive KRAS mutations to identify promising cancer therapeutics. Jun 21, 2024 · In conclusion, KRAS G12V inhibitors are at the forefront of targeted cancer therapy development, offering new hope for patients with KRAS-mutant tumors. Case reports using adoptive T-cell therapy provide proof of principle that KRAS G12D can be successfully targeted by the immune system in patients with cancer. Aug 26, 2022 · Patient-derived xenograft and cell-line models were subsequently used to show that KRAS G12V, as well as KRAS G13D, NRAS Q61K, NRAS G13R, MRAS Q71R or BRAF G596R mutations, conferred resistance to Aug 4, 2022 · Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. Dec 11, 2024 · Medigene AG, a leading innovator in immuno-oncology, has announced the selection of KRAS G12V as the first target for its T cell receptor-guided T cell engagers (TCR-TCEs). NSCLC with the KRASG12V muta-tion has distinct metastatic mechanisms compared with other subtypes, which can drive metastasis in a Wnt-dependent man-ner [8]. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 Sep 1, 2019 · Several new strategies, such as covalently targeting mutant KRAS, inhibiting KRAS interaction with associated proteins required for membrane association, inhibiting KRAS-driven malignant phenotypes and KRAS synthetic lethal interactions, have showed some promise in cancer therapy and may open new window for KRAS targeted anticancer drugs 4. 5 %), and lung (5. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. This phase I trial enrolls a total of 174 participants with various solid tumors. The two most common KRAS mutations are called G12D and G12V. CD8α/β coreceptor enables a coordinated CD4+/CD8+ T cell response and FAS-41BB converts the FAS ligand (FASL The heterogeneity of tumours could provide intrinsic mechanisms of resistance. " Cancer Discovery (2023): OF1-OF13. KRAS G12V is one of the most frequently mutated genes in cancer, often with the KRAS G12V peptide for 10 days, used FACS to sort HLA- A*11:01‒KRAS G12V tetramer-positive T cells for single-cell TCR sequencing, and found that the expansion of clones 1, 2, and 5 was Mar 22, 2024 · Abstract. May 5, 2024 · T-cell receptors (TCR)αβ and antibodies have been isolated that specifically recognize mKRAS encoded epitope(s) or haptenated-mKRAS peptides in the context of HLA-I on tumor cells. 84 months vs. 9 %) cancers. Small molecule Jan 5, 2022 · AbstractKirsten Rat Sarcoma (KRAS) gene somatic point mutations is one of the most prominently mutated proto-oncogenes known to date, and accounts for approximately 60% of all colorectal cancer cases. KRAS G12C mutations represent about May 25, 2023 · The success of finding allele-specific covalent KRASG12C inhibitors recently has made markedly breakthrough in KRAS targeted therapy, and has accelerated the discovery of agents targeting other KRAS mutants, such as G12D and G12V. 19 Currently, there are multiple ongoing early-phase clinical trials evaluating TCRs in CRC, including NCT0610521 and NCT06043713 for KRAS G12V, and NCT03948763 for KRAS G12D. The company also initiated the combination phase of its ongoing Phase 1 trial evaluating QTX3046, a G12D-selective KRAS inhibitor, with cetuximab, an EGFR inhibitor. For example, one tumour may contain 95% KRAS G12C and 0. 5% of all KRAS mutations, respectively. Despite advances, the five-year survival rates remain dismally low, with only a fraction of patients eligible for potentially curative surgical interventions. However, The first-line clinical treatment regimen for KRAS-mutant NSCLC patients remains similar to that for patients without driver genes, primarily involving immunotherapy combined with chemotherapy, where bevacizumab plays a significant role. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. Background Mutations in the RAS family are highly prevalent in human cancers, including up to 35% of non-small cell lung, 45% of colorectal, and 95% of pancreatic cancers. Of the trial that contains KRAS G12A as an inclusion criterion, 1 is phase 1 (1 open). Dec 9, 2022 · Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. KRAS was considered undruggable due to its high resistance to small molecule modulation. What’s exciting about this approach is that it “combines targeted therapy with immunotherapy,” said Kevan Shokat, Ph. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. 90% of pancreatic cancers exhibit KRAS G12D and KRAS G12V mutations that are currently considered “difficult to target”, due to the protein being chemically intractable [5]. 6. Multivariate The specific intracellular targeting of KRAS G12V RNA is mainly due to the extension of internal guide sequence (IGS) and addition of P10 and antisense sequences in the ribozyme. The protein has a smooth surface with no well-defined pockets for inhibitor binding, except for its GTP/GDP-binding pocket, which is occupied by GTP with Feb 1, 2024 · “This was a major breakthrough after decades of trying to find a good KRAS therapy,” Dr. 7 months; p = 0. Upon treatment with an allele-specific KRAS-G12C inhibitor, the tumour will regress but ultimately the KRAS G12V cells will be selected for and the Jan 19, 2021 · An analysis of 43 KRAS mutant NSCLC patients who were enrolled in the BATTLE-1 (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial determined that KRAS mutation variants G12C and G12V were significantly associated with worse median PFS compared to other KRAS variants or wild-type KRAS (1. Jan 15, 2023 · Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with Nov 6, 2024 · Recently, an emergency approval from the US-FDA has been issued for KRAS G12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. KRAS and Targeted Therapy 3. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. Leveraging Affini-T’s TETHER platform, we Aug 30, 2021 · KRAS mutations include G12V, G12F, G12D, G13X and Q61X. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. “But KRAS -G12C mutations are present in only 1% of pancreatic cancers. D. Methods KRAS mutant NSCLC patients received chemotherapy or immunotherapy as first-line treatment Nov 6, 2024 · BOSTON, MA – November 6, 2024 – Affini-T Therapeutics, Inc. 2 The high prevalence of KRAS aberrations in GI malignancies was crucial in promoting studies Aug 8, 2018 · Selective targeting of KRAS c. Quanta’s KRAS inhibitor pipeline Jul 18, 2024 · The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. Of the trials that contain KRAS G12V as an inclusion criterion, 3 are phase 1 (3 open) and 3 are phase 1/phase 2 (2 open). By focusing on chromosomal abnormalities and various indications of cancer, these medications have paved the way for the precise treatment of malignant tumors. Preclinical data suggests that KRAS mutations may confer resis- May 1, 2024 · The RAS gene family consists of KRAS, HRAS, and NRAS, which encodes membrane-associated 21 kDa proteins with guanosine triphosphatase (GTPase) activity [1,2]. May 29, 2024 · Single treatment of MRTX1133 caused a decline in CXCL8/IL-8 levels by 30% while single treatment of 5-FU showed a 36% decrease, the combination of both resulted in more than 55% decrease compared to control in LS513 KRAS G12D cell line. 35 G > T by CRISPR/Cas9 in CRC cell lines. Here, we investigated the clinical efficacy and prognosis those two regimens as first-line treatment in real-world practice. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. In this article, we focus on the therapeutic strategies targeting KRAS- mutant CRC, while reviewing and elaborating on the discovery and physiology of KRAS. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and Jul 22, 2021 · Once considered “undruggable,” KRAS mutations were a thorn in researcher’s sides-until now. KRAS proteins are small proteins with a relatively smooth molecular surface without readily accessible binding pockets, with a high affinity for GDP/GTP and complex downstream pathways (5, 43, 44). 243 Diego-González et al. Bear and authors also reported an additional KRAS G12V-reactive, HLA-A*11:01–restricted TCR from one of the healthy donors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment. 1. 3. Dec 9, 2024 · In this context, Shen and colleagues conducted a comprehensive review assessing the impact of immunotherapy, chemotherapy, antiangiogenic therapy, and targeted treatments on mutation subtypes, suggesting that NSCLC patients with KRAS G12D, G12V, or G13C mutations may benefit more from immunotherapy than people with KRAS G12A or G12C mutations Aug 1, 2014 · A recent retrospective analysis of the BATTLE clinical trial (discussed below) found worse progression-free survival for the group of patients with either KRas G12C or G12V, compared to other KRas mutants, or wildtype (1. 1% KRAS G12V cells. The NCCN guidelines include sotorasib and panitumumab, as well as adagrasib and cetuximab. We will discuss the efficacy and toxicities of the novel KRAS G12C inhibitors as well as other indirect strategies for targeting oncogenic KRAS mutations. In Sep 1, 2024 · These findings validate the potential of KRAS G12V blockade through our technology and propose them as a novel targeted cancer therapy. ” The new vaccine is able to activate immune cells that target different KRAS mutations called KRAS -G12D and KRAS -G12R, which drive about 90% of pancreatic Apr 12, 2022 · The story of characterizing RAS family proteins (NRAS, HRAS, and KRAS) that led to the first targeted therapy for KRAS-mutated lung cancer has been an impressive tour de force: a culmination of decades of iterative, persistent scientific investigation, punctuated with breakthrough insights, by researchers along the basic-to-clinical, bench-to-bedside, academia-to-industry continuum. 84 versus 3. , 7 Sep 22, 2024 · These findings from the phase 3 KRYSTAL-12 trial (NCT04685135), presented at the 2024 ESMO Congress, evaluated 453 patients who had previously received treatment with platinum-based chemotherapy and anti–PD-(L)1 therapy. ” Because cancer adapts, KRAS inhibitors alone have not generally been able to eliminate tumors, and often the cancer cells become resistant to the drug. 24,32,40 Negligible nonspecific transgene induction in cells is mainly due to the stable RNA structure inherent to the catalytic core region of the ribozyme, which Aug 21, 2024 · Signal Transduction and Targeted Therapy - MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer KRAS G12V, but not G12D was found to phosphorylate ERK Dec 1, 2024 · For the analysis of viability of Capan-1-KRAS G12V cells using various targeted therapies, Capan-1-KRAS G12V cells (3 × 10 3 cells/well) were seeded in a 96-well plate. To this date there is no Apr 1, 2016 · Although the G12V mutation is considered to be one of the most frequent KRAS codon 12 mutations in colorectal cancer patients—particularly in those with liver metastasis (ranging from 20. Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated RAS oncogene and patients with KRAS mutations have poor responses to standard treatment regimens. & Banerji, U. In this commentary, we advance the notion that mutant KRAS (mKRAS) is an ideal tumor neoantigen that is amenable for targeting by the adaptive immune system. In addition, smokers tend to have genetically more complex KRAS-mutant tumors, with higher mutational burden and higher frequency of major co- Apr 23, 2024 · The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. The reason for this bias is unclear, although evidence suggests that the KRAS G12R oncoprotein has distinct biochemical properties and is less A cell line from a tumor with a KRAS codon G12V mutation was unresponsive to cetuximab and panitumumab, whereas cell lines from a tumor with a KRAS codon G13D mutation showed an intermediate responsive to cetuximab and panitumumab in comparison with resistant KRAS codon mutation G12V and wild-type cells . Jun 1, 2024 · The combination gene therapy of pKRAS and siSLC achieved higher KRAS-G12V editing and SLC25A22 silencing efficiency, inducing stronger inhibition on apoptosis and proliferation KRAS-G12V mutant tumors. et al. Background: Both colorectal and pancreatic cancers are major global health issues and among deadliest cancers with great disease burden. Methods We Sep 25, 2024 · Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality in the United States, presents significant treatment challenges due to its late diagnosis and poor prognosis. 244 found that lipoplexes of si-FOSL-1 and si-YAP reduce the tumor growth in mice carrying tumors induced by Given there are no KRAS targeted therapies for KRASG12V Lopez, J. This move marks a significant step in its collaboration with WuXi Biologics, aimed at developing cutting-edge therapies to tackle difficult-to-treat cancers Oct 31, 2022 · In the UCSF study, the researchers engineered an antibody that helped kill cancer cells that were resistant to an experimental KRAS-targeted drug known as ARS1620. The most commonly mutated oncogenic alteration in human cancers is KRAS, which is prevalent in pancreatic malignancies. 35 months [P=0. Jan 31, 2024 · At the end of 2023, KRAS G12C–targeted therapy was added to the NCCN guidelines for CRC. Keywords: colorectal cancer, KRAS mutation, targeted therapy. Therefore, even if the treatment appears to initially work, the cancer can relapse. In the physiological state, when RAS receives an upstream signal from receptor tyrosine kinases (RTK), it is converted from a guanosine diphosphate (GDP)-bound inactive form to a GTP-bound active form, which activates several downstream print on KRAS, since transition mutations (G12D) are more frequent in never smokers, whereas transversion mutations (G12C and G12V) are more often found among former or current smokers [9, 10]. 5% to 32. 95 months) . However May 31, 2023 · AFNT-211 is an autologous T cell therapy engineered to express an HLA-A*11:01 KRAS G12V-specific TCR, further enhanced with CD8α/β coreceptor and a FAS-41BB switch receptor to drive T cell persistence and durable clinical responses. KRAS G12D and KRAS G12V are most prevalent, at 39. The present case suggests that the KRAS G12V mutation was present in a minute subclone and that the combination therapy caused the selective outgrowth of the KRAS G12V-positive subclone, leading to tumor progression through the activation of the PI3K/AKT/mTOR pathway . Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. KRAS inhibitors. Unlike mutations in the epidermal growth factor receptor (EGFR), KRAS mu-tations are not enriched in life long non-smokers [6]. Rev. Key Content and Findings. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications. The immunotherapeutic agents and targeted therapeutic agents currently under research, and their effects on the upstream and downstream pathways An accurate and timely result is the foundation of targeted KRAS inhibitor treatment. , of UCSF, who co-led the study. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab, were developed. S. There are other types of RAS mutations, but right now, targeted treatment is only available for KRAS in patient withs lung cancer and specifically for one type of KRAS mutation called a G12C mutation. KRAS mutations may be a potential biomarker for predicting the survival benefit of immunotherapy. Here, we describe a case of a 77-year-old male with KRAS G12V-mutant lung adenocarcinoma whose osteoblastic bone response was found during treatment with sintilimab and bevacizumab. Nov 1, 2024 · These TCRs targeted KRAS G12V in the context of HLA-A*03:01 or HLA-A*11:01, which are common HLA alleles found in individuals identified as White, Black, and Asian in the US. 046], vs. In the inhibition of RAS‐related pathway, it is showed that cotreatment with trametinib and osimertinib resensitizes the EGFR mutant NSCLC cell line with KRAS G12V to osimertinib. KRAS signaling. used doxycycline-inducible CRISPR/Cas9 as a therapeutic tool to target KRAS G12V, G12D, and G13D in CRC cells both in vitro and in vivo, demonstrating that a 7. Direct Targeting of KRAS G12C 3. 001). In SW480 KRAS G12V cell line, combination of 5-FU & MRTX1133 showed 30% inhibition while in Capan-2 PDAC KRAS Jan 31, 2024 · Mutations in the KRAS gene are among the most common mutations observed in cancer cells, but they have only recently become an achievable goal for targeted therapies. De Roock et al. 2 and 32. By specifically targeting the KRAS G12V mutation, these inhibitors have the potential to significantly improve treatment outcomes in cancers such as non-small cell lung cancer, colorectal In other ways, sequential administration of cell-cycle kinases CDK4 and CDK6 inhibitors after taxane treatment reduced cell proliferation in PDAC mouse model with both KRAS G12V and Cdkn2a-null mutations. 9 months mPFS in 2L treatment of bev-naïve KRAS-mutant mCRC. KRAS normally acts like a light switch, toggling between being “on” and “off. Alternative KRAS siRNAs have Nov 4, 2024 · We could potentially salvage some [off-targeted treatment] failures by moving to an on-targeted agent, especially because KRAS G12C amplification is a driving force for many of these resistance May 31, 2023 · KRAS was one of the first cancer genes ever discovered, but for a long time the cancer-causing KRAS protein was considered “undruggable” with targeted therapy. Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. , of NCI’s Center for Cancer Research, who was not involved with the new study. 270 A clinical study revealed that patients in the treatment of taxane cooperating with bevacizumab had higher objective response rate (ORR) than those treated with Jan 2, 2025 · For example, T cells engineered from the peripheral blood to target KRAS G12D and KRAS G12V mutants are undergoing trials for rectal and pancreatic cancers (NCT03745326 and NCT03190941). Recent progress highlights key advances on various fronts that validate mKRAS as a molecular target and support further pursuit as an immunological target. Nov 4, 2024 · Mutations of KRAS G12V variant from NSCLCs non-sensitive to Sotorasib. INTRODUCTION. The use of targeted drugs in clinical A phase I study of mRNA-5671/V941 as a monotherapy and in combination with pembrolizumab in KRAS mutant advanced NSCLC, colorectal cancer or pancreatic adenocarcinoma is now ongoing (NCT03948763) and uses the mRNA-derived KRAS-targeted vaccine V941 that targets certain KRAS mutations (G12D, G12V, G13D and G12C). Off-target effects are concerning for siRNA-based therapies, as siRNAs can bind mRNAs despite one or two sequence mismatches, which may lead to generalized cell toxicity even in healthy tissue . A separate Phase 1 trial Jan 4, 2024 · Quanta’s KRAS inhibitor pipeline includes three programs: QTX3034, a multi-KRAS inhibitor with G12D-preferring activity (G12D+ multi-KRAS), anticipated to enter clinical trials in 1Q24; QTX3046 Apr 25, 2024 · Targeted therapy is a well-established treatment strategy for lung adenocarcinoma with driver mutations . ceftv lelxrtf snqxzi vwfuaoe bvama fenvl kix tkmxl bojiped hzz