MRTX1133 / BMS - LARVOL DELTA

CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer. (PubMed, Cell) - "Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-γ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • IFNG • IL21 • KRAS

Pharmacological Inhibitors of Mutant Ras: Preclinical Studies, Biomarkers of Response and Rational Design of Combination Regimens. (IMS 2026) - "We thus evaluated the efficacy of inhibitors targeting specific KRAS mutants (e.g., G12C [MRTX-1257]; G12D [MRTX-1133]), a broader spectrum of KRAS mutants (BI-2865), or multiple mutant and wild-type RAS forms (e.g., RMC-6236 and RMC-7977) in preclinical models of MM...Finally, using in vitro pharmacological screening, we identified sensitizers and confirmed in vivo (NSG mice) that RMC-6236 combined with lenalidomide is more active than either agent alone. These findings map the complex molecular landscape underlying Ras inhibitor responses and can inform personalized clinical development of these agents in MM. ( authors with equal contribution)"

Preclinical • Solid Tumor • FGFR3 • IL6 • KRAS • NRAS • PPIA

Integration of Patient-Derived Organoids and Multiomics Profiling (IASGO 2026) - "First-line selection between FOLFIRINOX and gemcitabine plus nab-paclitaxel still rests onage and performance status rather than tumor biology...Transcriptomic and epigenomic layers addbiology that DNA misses, yet subtyping predicts group prognosis rather than individual drug sensitivity.Direct RAS inhibition has changed this landscape: in RASolute 302, daraxonrasib doubled medianoverall survival against second-line chemotherapy...Organoids also expose vulnerabilities genomics cannot, such as MRTX1133 synergizedwith anti-EGFR agents only in KRAS G12D tumors...Co-culture with cancer-associated fibroblasts, endothelial cells, and immunecells, and microfluidic patient avatars restore these interactions. The endpoint is a patient avatar thatreconstructs the microenvironment and, read together with multiomic profiles, returns an actionablereport within a clinically useful window."

Clinical • Microsatellite Instability • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • KRAS • MSI • TMB

CD24 promotes development of KRAS-mutant lung adenocarcinoma and response to KRAS-targeted therapy (AACR 2025) - "Analysis of publicly available datasets showed that KRASG12C inhibitor MRTX1257 also increased Cd24a expression in mouse tumor cells with KRAS p.G12C mutations. In syngeneic mice with KrasG12C/+; Tp53R172H/+ KM-LUAD cells, sotorasib treatment enhanced CD24 protein levels in tumors compared to controls...Syngeneic mice treated with MRTX1133 and anti-CD24 antibodies showed greater KM-LUAD reduction than single agents or controls...Similarly, combining KRASG12C inhibitor adagrasib with anti-CD24 antibody in syngeneic mice reduced KM-LUAD growth more than single treatments or controls. Our findings demonstrate that CD24 drives KM-LUAD progression from its earliest stages and contributes to adaptive resistance to KRAS inhibition. Targeting CD24 in combination with KRAS inhibitors, represents a promising strategy for treating and intercepting KM-LUAD."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD24 • GPRC5A • KRAS

Beyond KRASG12C: emerging therapeutic strategies, patent landscape, and clinical progress in targeting KRAS-mutant cancers. (PubMed, Med Oncol) - "For most of its history, KRAS has been regarded as "undruggable." Still, with recent developments in covalent inhibitors targeting KRAS^G12C, specifically sotorasib and adagrasib, it has now been validated as a viable therapeutic target...New classes of KRAS inhibitors have recently emerged, including non-covalent inhibitors (MRTX1133, RMC-9805), pan-RAS (ON) antagonists (RMC-6236), and KRAS-directed degraders (ASP3082), as well as planned rational combinations of these new KRAS inhibitors with agents targeting SHP2, SOS1, MEK, and immune checkpoint inhibitors...The regulatory environment and commercialization efforts present opportunities and challenges for precision oncology in KRAS-driven cancers globally. Overall, the rapid evolution of KRAS-targeted therapeutic agents represents a shift from allele-specific inhibition towards a strategy that is mutation/context-dependent, thereby creating further clinical translation opportunities and increased patient..."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

XPO1 inhibition enhances the efficacy and durability of RAS-targeted therapy in preclinical models of KRASG12D mutant pancreatic ductal adenocarcinoma. (PubMed, Cancer Lett) - "Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC."

IO biomarker • Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • XPO1

IRE1α-XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma. (PubMed, Proc Natl Acad Sci U S A) - "Importantly, the IRE1α RNase inhibitor B-I09 clearly synergized with MRTX1133 in vitro and in vivo, moreover, this is likely due to MYC-fatty acid synthase (FASN) dysregulation. Together, these findings identify context-dependent vulnerabilities of the IRE1α-XBP1s pathway in PDAC and provide a rationale for combining inhibition of IRE1α and KRAS to enhance therapeutic responses."

Journal • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • FASN • KRAS • XBP1

Identification of the Potential of Plant-Derived Agents to Act as KRAS G12D Inhibitors Through Molecular Docking, Molecular Dynamics Simulations, and MMGBSA. (PubMed, Curr Pharm Des) - "As a result of this in silico study, coniferin, neochlorogenic acid, and chlorogenic acid have been identified as potential precursor molecules for KRAS G12D inhibition. Isochlorogenic acid was excluded due to its dynamic instability. These plant-derived compounds require further experimental validation as potential anticancer agents targeting KRAS G12D mutations."

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

Effects of the KRAS (G12D)-selective inhibitor MRTX1133 in ovarian mucinous carcinoma (ESGCT 2026) - No abstract available

Mucinous carcinoma • Oncology • Ovarian Cancer • KRAS

Emerging Therapeutic Strategies for Non-G12C KRAS Mutations in Colorectal Cancer: Focusing on G12D and G12V. (PubMed, J Gastrointest Cancer) - "The non-G12C KRAS era is beginning, but durable benefit in CRC will likely require rational combinations tailored to allele, lineage, and resistance biology."

Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Fibroblast Activity and Collagen Deposition: Liquid Biomarkers to Track KRAS-induced Tumor Fibrosis and KRAS Inhibitor Efficacy in NSCLC (IASLC-WCLC 2026) - "ScRNAseq data from KPPC mice treated with KRAS inhibitor MRTX1133 were analyzed using standard Seurat v5 workflow...Integrating KRAS mutation status with myCAF-derived collagen biomarkers provides a more comprehensive framework to understand tumor-stroma interactions in NSCLC. This combined approach has the potential to improve patient stratification, identify mechanisms of resistance to KRAS-targeted therapies, and guide the development of combination strategies targeting both tumor cells and the fibrotic microenvironment."

Biomarker • Clinical • Fibrosis • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • COL11A1 • COL12A1 • COL1A1 • COL3A1 • COL5A2 • COL8A1 • KRAS • TGFB1

Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer. (PubMed, Nat Commun) - "Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • KRAS

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • 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

MRTX1133 ligand binding converges GDP- and GTP-bound K-RasG12D into a joint conformational ensemble as depicted by NMR spectroscopy | Poster Board #1199 (ACS-Fall 2026) - "Our data reveal that MRTX1133 binding markedly reduces the overall plasticity of K-RasG12D, largely suppressing Switch II dynamics while leaving limited residual motions in Switch I. RDCs and order parameters (S2) further show that MRTX1133 locks K-RasG12D into one common conformational state, whereas the free GDP- and GTP-bound forms of K-RasG12D differ substantially. These results reveal the dynamic mechanism of K-RasG12D inhibition at atomic detail and provide a framework for rational design of KRAS-targeted therapeutics"

KRAS

Discovery of a Potent and Selective KRAS G12D Degrader based on PROTAC Degradation. (PubMed, Eur J Pharm Sci) - "In this study, we designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative...Notably, the preferred compounds exhibited significant selectivity for other KRAS mutations and normal cells. This work provides an important lead compound for developing highly selective KRAS G12D PROTACs and warrants further exploration in the context of drug-likeness optimization."

Journal • Targeted Protein Degradation • KRAS

Targeted KRAS suppression in colorectal cancer via in vivo self-assembled siRNAs encapsulated in endogenous small extracellular vesicles. (PubMed, J Control Release) - "Tandem circuits co-expressing two siRNAs exhibited synergistic and superior efficacy compared to single-siRNA circuits or the small-molecule inhibitor MRTX1133...Comprehensive safety evaluation revealed minimal off-target effects and no detectable systemic toxicity, highlighting the favorable safety profile of the platform. Collectively, this study establishes a robust and targeted siRNA delivery system that effectively overcomes the historical limitations of KRAS targeting, providing a promising therapeutic strategy for a broad spectrum of KRAS-driven cancers."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Concurrent Stereotactic Body Radiation Therapy and KRAS Inhibition Synergistically Improve Pre-clinical Pancreatic Cancer Treatment. (PubMed, bioRxiv) - "In this study, we investigated the combination of stereotactic body radiation therapy (SBRT) and KRAS inhibition (MRTX1133 and daraxonrasib) in the treatment of preclinical PDAC models. Our study indicates that this SBRT-KRASi combination has the potential to overcome treatment resistance and improve outcomes in PDAC patients. These data directly support the design of a planned multi-center Phase 2 clinical trial with this combination strategy in locally advanced PDAC."

Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PDX1 • TP53

KRASG12D inhibition reprograms the tumor-induced immunosuppressive environment and enhances NK cell-mediated antitumor immunity. (PubMed, Sci Adv) - "Consequently, combining MRTX1133 with IL-15 or adoptive NK cell therapy yields synergistic antitumor responses and prolonged survival. Our findings provide mechanistic rationale for combining KRASG12D inhibitors with NK cell-based immunotherapies to improve outcomes for patients with KRASG12D-mutant cancers."

IO biomarker • Journal • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • ICAM1 • IFNG • IFNGR1 • IL15 • KRAS • ULBP1

CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC. (PubMed, EMBO J) - "Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRASG12D inhibition by MRTX1133 initially increases CD11c+ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance."

Biomarker • IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ITGAX • KRAS

Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment. (PubMed, Gut) - "In summary, SMPD1 regulated plasma membrane sequestration of KrasG12D represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC."

Journal • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

KRAS inhibition is an effective therapy for appendiceal adenocarcinoma. (PubMed, J Hematol Oncol) - "While effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT pathway may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support the continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling."

Journal • Appendix Cancer • Immunology • Oncology • Peritoneal Cancer • CAFs • IFNG • KRAS • PDX1

In Silico identification of natural and synthetic inhibitors targeting KRAS mutants (G12D, G12V, and G12C) and wild-type in pancreatic cancer. (PubMed, J Mol Graph Model) - "Several compounds, including Pirbuterol, Levonordefrin, Mugineic acid, Irilin D, DH-DMX, and DXP, demonstrated favorable binding affinities relative to reference inhibitors MRTX1133, Daraxonrasib, and Adagrasib. Notably, Levonordefrin showed consistent binding across multiple KRAS variants. These findings identify potential candidates for further experimental validation and support the application of computational approaches in KRAS-targeted drug discovery for Pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

USP20 promotes CD8+ T cell exhaustion and impairs KRASG12D inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer. (PubMed, Gut) - "USP20 acts as a critical metabolic checkpoint that orchestrates CD8+ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRASG12D inhibitors in PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • CD8 • EGR1 • KRAS • USP20

Palbociclib targets β-catenin for degradation and synergizes with KRAS or ERK5 inhibition in colorectal cancer preclinical models. (PubMed, J Transl Med) - "Together, these findings position palbociclib as a versatile therapeutic backbone in CRC. By simultaneously targeting cell cycle and oncogenic signaling networks, palbociclib-based combinations induce synergistic and durable responses, offering a compelling rationale for tailored therapeutic strategies in molecularly defined CRC."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • CREB5 • CTNNB1 • KRAS