MRTX1133 / BMS - LARVOL DELTA

Functional genomics studies identify determinants of response vs. resistance to pharmacological inhibitors of KRAS in multiple myeloma (ASH 2025) - "We evaluated Rasinhibitors in preclinical models of MM, with emphasis on genome-scale CRISPR studies to define themolecular determinants of response and resistance to these agents.We studied selective inhibitors of KRAS G12C (MRTX-1257) or G12D (MRTX-1133) mutants; the broaderspectrum mutant-KRAS inhibitor BI-2865; or the tricomplex pan-Ras inhibitor RMC-6236. Notably, even MM cells with the same KRASmutation can display distinct "resistomes", highlighting the complex functional genomic landscapeunderlying Ras inhibitor responses. We envision that these results will inform personalized uses of Rasinhibitors in future clinical studies in MM."

Genomic study • Hematological Malignancies • Multiple Myeloma • Solid Tumor • ABCB1 • DUSP6 • EGFR • FGFR3 • IL6 • KEAP1 • KRAS • LZTR1 • NRAS • PPIA

HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis. (PubMed, J Clin Invest) - "Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on "KRAS-MYC dual-node blockade." Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as potential biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC."

Journal • Gene Therapies • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • HDAC5 • KRAS • MYC • NEDD4

Actionable mutations in pancreatic cancer: where targeted therapies are making a difference. (PubMed, BMJ Open Gastroenterol) - "It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the..."

Journal • Review • Gene Therapies • Microsatellite Instability • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • HER-2 • KRAS • MSI • MTAP • NRG1 • NTRK

A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. (PubMed, Proc Natl Acad Sci U S A) - "Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EGFR • KRAS • TP53

Targeting Mutant KRAS with Novel Mutant-Specific Pharmacological Inhibitors: Activity Against Myeloma and Other Lymphoid Malignant Cells and Molecular Mechanisms of Resistance (ASH 2023) - "We assessed the activity of novel G12C- (MRTX1257) and G12D- (MRTX1133) specific pharmacological KRAS inhibitors against 2 MM lines with G12C (KHM1B, XG7) and 2 with G12D (KARPAS620, KP6) KRAS mutations; as well as the G12D mutant KOPN-8 (B-ALL) and CCRF-CEM (T-ALL) lines...melphalan, bortezomib, pomalidomide, trametinib) caused in some cases supra-additive effects, but – more importantly – showed no antagonism with any combination...This study also provides functional evidence about genes and molecular pathways that regulate MM cell sensitivity vs. resistance to KRAS inhibitors. These results create a framework for ongoing and future efforts to translate the use of KRAS inhibitors into clinical studies for MM and other lymphoid malignancies."

Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • ANXA5 • DUSP6 • EGFR • ETV4 • ETV5 • KRAS

Functional Genomics Studies Decipher the Genetic Perturbations and Unravel Mechanisms of Response/Resistance upon Mutant-Specific KRAS Inhibition in Multiple Myeloma (ASH 2024) - "METHODS : We performed a total of 11 genome-scale CRISPR gene activation or CRISPR gene editing (knockout, KO) studies in 5 MM lines with distinct KRAS point mutations (KHM-1B and XG-7 [G12C]; KARPAS-620 and KP-6 [G12D]; or MM.1S [G12A]) after treatment with specific KRAS inhibitors (MRTX-1133, MRTX-1257, BI-2865, RMC-6236) in clinically achievable concentration ranges (as used in patients with solid tumors). These compounds exhibit potent and specific activity against MM cells with the respective KRAS mutations, but our functional studies point to individual lines, even those harboring the same KRAS mutation, exhibiting their own distinct "resistome" against these inhibitors. These results underscore the complex functional genomics of MM cell sensitivity vs. resistance to KRAS inhibitors and have implications for the choice of potential combination partners of these inhibitors in future preclinical or clinical studies."

Genomic study • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • ANXA5 • DUSP6 • EGFR • ETV4 • ETV5 • KEAP1 • KRAS • LZTR1

KRAS G12D Specific Inhibitors Relieve Erythroid Differentiation Block and Modulate Inflammatory Pathways at the Single Cell Level in Myeloid Malignancies (ASH 2024) - "To test the impact of KRAS-targeted therapy on isolated KRASG12D clones (without confounding co-occurring mutations), we treated the KRASG12D CH sample with a clinically valid KRASG12D inhibitor MRTX1133 and a pan-KRAS inhibitor BI-2865...These data support investigations of KRASG12D inhibitors in myeloid malignancy clinical trials. Ongoing studies test the efficacy of in vivo targeting of KRASG12D clones in murine and xenograft models."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CD83 • CXCL3 • CXCL8 • ETV6 • GYPA • IL6 • JARID2 • KRAS • RUNX1 • TFRC • ZEB2

Targeting Acquired Resistance to KRASG12DInhibitors: designing rationale synergistic treatments. (AACR-NCI-EORTC 2025) - "Interestingly, co-treatment of MRTX133 with MG-132 or bortezomib- potent proteasome inhibitors- or dactolisib -dual PI3K and mTOR inhibitor- increased cleaved PARP levels...Thus, drug resistant models were sensitive to dual MRTX1133 and patritumab deruxtecan inhibition...More importantly, these drug combinations were also effective in sensitive and de novo MRTX1133 resistant patient-derived organoids. Our findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD24 • ERBB3 • KRAS • STAR

VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with superior anti-tumor efficacy relative to ON-only KRAS inhibitors (AACR-NCI-EORTC 2025) - P1/2 | "In 3D proliferation assays among a panel of human tumor cell lines, VS-7375 showed improved KRAS G12D potency and selectivity relative to the G12Di RMC-9805 and MRTX1133...To assess potential benefits of dual ON/OFF inhibition in KRAS G12D in vivo models, we compared efficacy relative to the ON-only inhibitors RMC-9805 (G12Di) and RMC-6236 (pan-RAS inhibitor)...Combination of VS-7375 with the anti-EGFR antibody cetuximab induced complete responses in all mice in a colorectal cancer xenograft model, and cetuximab also augmented the antitumor efficacy of VS-7375 in pancreatic and lung cancer models...VS-7375 is now being evaluated as monotherapy and in combinations in the US (NCT07020221). Altogether, these results demonstrate that the dual ON/OFF profile of VS-7375 corresponds with strong preclinical anti-tumor efficacy in KRAS G12D mutant cell lines and animal models, along with promising initial response rates for patients with KRAS G12D mutant solid tumors."

Clinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Dual targeting of BET and EP300 with XP-524 in pancreatic cancer lines resistant to KRAS inhibitors (AACR-NCI-EORTC 2025) - " We treated PDAC cell lines, Panc1 and AsPC1, with KRAS-G12D inhibitor (MRTX1133), selecting surviving cells after each passage...The concentration-response of both parent and resistant cell cultures was assayed after treatment with XP-524, pan-KRAS inhibitor (BI-2865), RAS-ON inhibitor (RMC-6236), or KRAS G12D inhibitor (RMC-9805), measuring antiproliferative potency and both mRNA and protein expression... Panc1-MR cells were resistant to all evaluated KRAS inhibitors in clinical development, showing no response to KRAS inhibitors below 1 µM concentration. Small right shifts in concentration-response were seen for all inhibitors in AsPC1-MR cells. XP-524 retained efficacy as an antiproliferative agent in kinase-resistant PDAC cells, with a small right-shift in antiproliferative potency in Panc1-MR cell cultures relative to parental cell lines."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EP300 • KRAS

Inhibition of KRAS-G12D as a radiosensitization strategy for KRAS-G12D-mutant pancreatic ductal adenocarcinoma cells (AACR-NCI-EORTC 2025) - "Combining the KRASG12D inhibitor MRTX1133 with irradiation induces synergistic cytotoxic effects in KRASG12D-mutant murine PDAC cells, warranting further testing of multimodality strategies to overcome resistance and improve therapeutic outcomes in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Hybrid nanovesicles enhance antitumor efficacy in KRAS-mutant non-small cell lung cancer. (PubMed, J Control Release) - "We evaluated this nanocarrier-based therapeutic strategy for delivering the KRASG12D inhibitor MRTX1133 in KRASG12D-mutant cell lines and animal models...Mechanistically, it reprograms the tumor microenvironment by sustaining MAPK and PI3K pathway inhibition, reducing EGFR phosphorylation, enhancing CD8+ T-cell infiltration, and restoring antitumor immunity through PD-L1 blockade. By exploiting the signaling vulnerabilities of KRAS-driven tumors, our hybrid nanovesicle platform provides a promising therapeutic strategy for overcoming resistance and improving therapeutic response in KRAS-mutant NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • KRAS

Dual Inhibitors of KRASG12D and HSP90 are Effective Against KRASG12D Inhibitor Resistance. (PubMed, Mol Cancer Ther) - "Our findings reveal that the efficacy of the clinical-stage KRASG12D inhibitor MRTX1133 varies, with notable resistance being observed in some cell line and organoid models...The rationale for targeting HSP90, which is preferentially activated in cancer cells, alongside KRASG12D, arises from the ability of HSP90 inhibition to destabilize substrate client proteins that are essential for cancer cell survival and have also been implicated in resistance to KRAS inhibitors. This dual inhibitor approach presents a promising new strategy to combat de novo and acquired drug resistance in KRASG12D-mutated cancers and potentially paves the way for improved clinical outcomes by addressing the complex molecular mechanisms underlying cancer cell evolution that enables resistance to conventional inhibitors."

Journal • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CDC37 • HSP90AA1 • KRAS

A Splicing Switch in ERK1 Controlled by SMNDC1 Drives MAPK Pathway Reactivation and Resistance to KRAS inhibitors in PDAC Free (AACRPanCa 2025) - "Notably, SMNDC1 expression and MAPK3 E4 inclusion were elevated in PDAC cells with acquired resistance to KRAS inhibitors (KRASi: RMC-6236, adagrasib, MRTX1133, and sotorasib) and MEK inhibitors (selumetinib, trametinib). Together, our findings identify a previously unrecognized splicing-based mechanism of MAPK activation and therapy resistance. SMNDC1-mediated MAPK3 E4 inclusion constitutes a tunable switch for ERK1 stabilization and oncogenic output, offering a novel therapeutic vulnerability in KRAS-driven PDACs."

Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • MAPK3

Targeting KRAS inhibitor-resistant pancreatic cancer with a MUC1-C antibody-drug conjugate. (PubMed, Clin Cancer Res) - "These findings demonstrate that M1C confers resistance of PDAC to KRAS G12D inhibition and identify M1C as a potential target for ADC treatment of PDAC patients who are refractory to KRAS inhibitors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MUC1

IDENTIFYING THERAPEUTIC VULNERABILITIES IN KRASG12D-RESISTANT PANCREATIC CANCER USING HIGH-THROUGHPUT DRUG SCREENING (UEGW 2025) - "Our study highlights the heterogeneity of KRASG12D-driven PDAC towards MRTX1133. Through high-throughput drug screening, we found that Nintedanib synergizes with MRTX1133 to overcome resistance in mesenchymal PDAC cell lines. These findings provide a potential combination strategy to improve therapeutic outcomes in KRASG12D-mutant PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • SMAD4 • TGFBR2 • TP53

DYSREGULATED SPHINGOLIPID METABOLISM DRIVES PANCREATIC CARCINOGENESIS BY INTERFERING WITH KRAS SIGNALLING (UEGW 2025) - "Notably, the SMPD1 inhibitor (ARC39) potently synergizes with the KrasG12D inhibitor (MRTX1133). In summary, SMPD1 regulated plasma membrane sequestration of KrasG12D represents a potential therapeutic target within the Kras signaling pathway for intractable PDAC. Targeting SMPD1 with Kras inhibitors, may provide effective strategies to mitigate cancer progression, recurrence and overcome treatment resistance."

Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Minimally invasive fluid-derived organoids enable modeling of chemotherapy resistance in pancreatic ductal adenocarcinoma Free (AACRPanCa 2025) - "Drug screening demonstrated that FDOs harboring KRAS G12D mutations responded to the KRAS inhibitor MRTX1133. Transcriptomic profiling identified a poor prognosis-associated gene signature that conferred gemcitabine resistance by suppressing apoptosis. Collectively, our findings establish FDOs as clinically relevant, minimally invasive, and scalable models that enable personalized therapy and biomarker discovery in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Respiratory Diseases • KRAS

Uncovering the dual roles of XBP1 in pancreatic ductal adenocarcinoma during lipid imbalance and KRAS inhibitor resistance Free (AACRPanCa 2025) - "Despite its cytotoxic role under lipid-deprived conditions, we discovered a contrasting function of XBP1 in mediating the survival of PDAC cells resistant to the KRASG12D inhibitor MRTX1133 (KRASi)...Ongoing work aims to determine the therapeutic potential of targeting XBP1 in KRASi-resistant PDAC and to identify the specific lipid species involved in mediating resistance. Additionally, although B-I09 rescues cell viability under lipid imbalance across both classical and basal PDAC subtypes, we are currently investigating whether these subtypes exhibit differential sensitivity to the combination of KRAS inhibition and B-I09."

Fibrosis • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ERN1 • KRAS • XBP1

Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity Free (AACRPanCa 2025) - "On this basis, combining ulixertinib or the KRAS^G12D inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan markedly suppresses the growth of PDAC patient-derived xenografts (PDXs). Together, our study uncovers TRIM22 as a molecular link between interferon signaling and EMT and nominates TROP2 as a druggable vulnerability that can be co-targeted to augment the therapeutic efficacy of KRAS-MAPK pathway inhibitors."

Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • KRAS • NFKBIA • TACSTD2 • TRIM22

Oncogenic KRAS drives nutrient transport to support growth in pancreatic cancer Free (AACRPanCa 2025) - "Although MRTX1133 (KRASG12D inhibitor) has demonstrated promise in targeting the KRAS/MAPK pathway, responses differ throughout PDAC subtypes, and resistance has been reported...CRISPR/Cas9-mediated knockout of SLC20A1 disrupted the Warburg effect in PDAC cells. In conclusion, our data suggests that KRAS/MAPK inhibition exert robust control on nutrient transport as a mechanism to impair metabolism in KRAS-reliant PDAC cells."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Oncogenic KRAS signaling mediates NF-kB induced chemokine production by pancreas tumor cell Free (AACRPanCa 2025) - "However, significant decreases in both chemokines were observed with cell line resistance or treatment with KRAS G12D (MRTX1133) and RAS-MULTI(ON) (RMC-7977) inhibitors. Lastly, inhibition of CCL20-CCR6 signaling in vivo with a novel CCR6 inhibitor, CCL20-locked dimer (CCL20LD) resulted in increased dendritic cells recruited to orthotopic KPC tumors in mice. Together, these data suggest that mutated RAS alone is responsible for production of chemokines that modify the PDA TME and that RAS inhibitor resistant tumors may have a less immunosuppressive TME."

Tumor cell • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pancreatitis • Solid Tumor • CCL20 • CCR6 • CXCL5 • DNMT1 • EGFR • KRAS

COMBINED TEAD AND RAS INHIBITOR THERAPY ACHIEVES LONG-TERM SURVIVAL IN KRAS-MUTANT CHOLANGIOCARCINOMA (AASLD 2025) - " Bulk and scRNA-seq analysis in mouse CCA models, the TCGA and Fu-iCCA cohorts and human scRNA-seq data revealed a consistent upregulation of YAP/TAZ/TEAD pathway members...VT104 or IAG933 plus KRASG12D-specific inhibitor MTRX1133 or panRAS inhibitors RMC-7977 and RMC-6236 blocked compensatory YAP/TAZ pathway activation, achieved strong synergies in vitro and extended median survival from 2.3 weeks to 9.7 weeks (VT104 + MRTX1133, p<0.0001) and 14.4 weeks (VT104 + RMC7977, p<0.0001) in KRASG12D-driven CCA... Collectively, our study identified TEAD and RAS signaling as convergent and druggable vulnerabilities that can be targeted to prolong CCA survival and delay the development of resistance."

IO biomarker • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CAFs • KRAS • NICD

Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant. (PubMed, J Med Chem) - "Subsequently, we incorporated the warhead onto MRTX-1133, a potent ligand of the KRAS (G12D) mutant, to generate a novel TCI called KN2-H...It also possessed strong antiproliferative activity against KRAS (G12D) mutant cell lines by downregulating RAS oncogenic signaling. Our findings provide a novel strategy for designing novel TCIs targeting carboxyl residues, based on acyl diazo warheads."

Journal • Oncology • KRAS

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation. (PubMed, bioRxiv) - "These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. VEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRAS G12D cancer cells Nuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant modelsInteraction of p110γ-p101 with KRAS activates PI3Kγ in the resistant models VEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo."

Journal • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KDR • KRAS • PIK3CG