MRTX1133 / BMS - LARVOL DELTA

Combining FGTI-2734 and MRTX1133 to suppress ERK-driven resistance in KRAS G12D pancreatic cancer (AACR 2026) - "Importantly, FGTI-2734 treatment prevented MRTX1133-driven ERK reactivation in these KRAS G12D xenograft models. Collectively, these results define a mechanistically grounded combination strategy that neutralizes a key resistance pathway limiting MRTX1133 efficacy, and they highlight a promising therapeutic option for KRAS G12D pancreatic cancers."

Oncology • Pancreatic Cancer • Solid Tumor • CDKN2A • KRAS • PI3K • SMAD4 • TP53

Rezatapopt and KRAS inhibitors for the treatment of TP53 Y220C and KRAS mutant cancers (AACR 2026) - "SRB assay showed that both MRTX1133 (KRAS G12D inhibitor) or daraxonrasib (RMC-6236, pan-RAS inhibitor) were synergistic with rezatapopt in two TP53 Y220C and KRAS G12D cell lines. Rezatapopt combined with KRAS inhibition increased antitumor activity. Further studies are needed to understand the mechanism of synergy."

Colorectal Cancer • Oncology • Solid Tumor • KRAS

Unveiling mechanisms of MRTX1133 resistance in PDAC models (AACR 2026) - "To investigate these mechanisms, we established resistant cell lines through stepwise escalation of MRTX1133, the first covalent inhibitor of KRAS G12D to enter clinical evaluation, in KRAS G12D-mutant modelsThese resistant cells maintain stable phenotypes to MRTX-1133 both in vitro and in vivo, and exhibited broad cross-resistance to other KRAS G12D inhibitors, such as RMC9805 and HRS-4642, with partial resistance observed toward the pan-RAS inhibitor RMC6236.Bioinformatic analysis of both resistant models revealed a spectrum of convergent adaptive mechanisms, including: (1) altered oncogenic signaling networks, (2) upregulation of cell cycle and drug efflux regulators, and (3) epithelial-mesenchymal transition (EMT). The established resistant models serve as physiologically relevant platforms for biomarker discovery and the development of rational combination therapies. Using these models, functional studies demonstrated that targeting core vulnerabilities—including..."

Oncology • KRAS

Ferroptosis induction synergizes with KRAS inhibitors in KRAS-mutant lung adenocarcinoma (AACR 2026) - "Whether ferroptosis resistance mediates resistance to KRAS G12C and G12D inhibitors in lung adenocarcinoma cells harboring these mutations is unknown. DepMap was used to retrieve the drug sensitivity data for RSL3, erastin, ML162, ML210, sotorasib, and MRTX1133 as well as CRISPR and RNAi screen data in NSCLC human cell lines. KRAS inhibition induces ferroptosis in KRAS-mutant lung adenocarcinoma cell lines and ferroptosis resistance correlates with resistance to KRAS inhibitors. Combining ferroptosis induction strategies could potentially enhance the effectiveness of KRAS targeting treatments."

Lung Adenocarcinoma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • STK11

Novel PCNA inhibitor AOH1996 synergizes with KRAS-targeted therapies in pancreatic ductal adenocarcinoma (AACR 2026) - "Across KRAS G12C and G12D models, AOH1996 exhibited strong synergy with KRAS inhibitors, including MRTX1133, sotorasib, adagrasib, and RMC-6236. AOH1996 is a promising therapeutic candidate for PDAC, demonstrating potent single-agent activity and strong synergy with clinically relevant KRAS inhibitors across in vitro, ex vivo, and in vivo models. The combination induces profound apoptotic and cell-cycle effects and disrupts key KRAS effector pathways. These results support further translational development of AOH1996-based combination regimens for patients with KRAS-mutant PDAC."

Oncology • Pancreatic Ductal Adenocarcinoma • ANXA5 • KRAS • PCNA

Design and discovery of BH-501242, a novel pan-KRAS on/off inhibitor targeting KRAS switch II pocket (AACR 2026) - "MRTX1133 was the first to demonstrate low single-digit nM cell potency for G12D mutation; however, the inhibitor lacked the ADME properties required for a successful oral drug...Synergistic effects were observed in combination with EGFR antibody cetuximab in colony formation assays with KRAS mutant cells. PK profiling revealed oral bioavailability of BH-501242 in multiple species and dose dependent plasma exposures in mouse xenograft tumor models. BH-501242 demonstrated excellent anti-tumor activity in multiple CDX mouse models with various KRAS mutations, including GP2D and HPAC models with G12D mutation, H441 with G12V, and MiaPaca-2 with G12C, etc. In conclusion, the strong preclinical profile provides a strong rationale for the advancement of BH-501242 into further development."

Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Adaptive and acquired mechanisms underlying RAS-mutant tumor response to mutant and state selective RAS inhibitors (AACR 2026) - "Recent advances in drug discovery have enabled the development of the pan-RAS(ON) inhibitor RMC6236, which uses a tricomplex strategy, as well as several KRAS-MUT-specific inhibitors (such as Adagrasib, Sotorasib, and MRTX1133) that target the OFF state. We also identified multiple cross-resistance patterns across different direct RAS inhibitors, highlighting the need for better mechanistic understanding to optimize RAS-inhibitor treatments for maximal therapeutic benefit. Together, our results provide mechanistic insight into resistance to direct RAS inhibitors in RAS-MUT cancers and emphasize the urgent need for improved strategies to treat patients who do not respond to current RAS-targeted therapies."

Oncology • KRAS

Prolonged KRAS-MAPK inhibition activates interferon signaling to promote cellular plasticity and uncover novel targets for combination therapy (AACR 2026) - "Combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan effectively suppressed growth of PDAC patient-derived xenografts. This study highlights TRIM22's role in linking interferon signaling with EMT and identifies TROP2 as a therapeutic vulnerability to overcome acquired resistance."

Combination therapy • Oncology • KRAS • NFKBIA • TACSTD2 • TRIM22

Combined RAS and ICB inhibition targets NF-KB-driven immune evasion in chemoresistant pancreatic cancer (AACR 2026) - "In addition, human PDAC organotypic slice cultures were treated with RMC6236 and immune checkpoint blockade (ICB). In vivo experiments tested MRTX1133 in combination with anti-CTLA-4 or dual anti-CTLA-4 + anti-PD1 therapy...Mechanistically, RASi in tumor cells activate NF-κB signaling, driving cytokine changes that enhance PD-1 and CTLA-4 expression in T cells. Targeting these NF-κB-driven cytokines and immune checkpoints alongside RAS inhibition represents a promising combinatorial strategy to overcome chemoresistance and improve PDAC outcomes."

IO biomarker • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCL2 • CXCL10 • KRAS

Elucidation and therapeutic strategies to overcome intrinsic resistance mechanisms in KRAS G12D-mutant tumors (AACR 2026) - "While SHP2 inhibition alone showed limited activity, its combination with MRTX1133 prevented ERK reactivation and achieved substantial growth suppression.[Discussion and Conclusion] Resistance to MRTX1133 in KRAS G12D-mutant tumors is driven by AXL and FGFR1 activation, which can be suppressed through dual or triple combination therapies. Inhibition of adaptor proteins such as SHP2 further provides a strategy to overcome heterogeneous RTK-mediated resistance, supporting combination approaches targeting adaptor signaling."

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

Acquired resistance to Tri-complex inhibitors in colorectal cancer (AACR 2026) - "For patients with advanced solid tumors harboring a KRAS G12D mutation, several selective inhibitors have entered clinical trials (MRTX1133, RMC-9805, QTX3034/46, LY3962673...) and RMC-6236, a pan-RAS inhibitor from Revolution Medicines, has recently shown promising early clinical data. This resistance can still be addressed by other KRAS G12D inhibitors, opening options for patients harboring this characteristic post RMC-therapy. Future investigations may focus on characterizing tumors from patients who relapse on RMC-6236 and RMC-9805 to validate these findings clinically."

Preclinical • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Predicting resistance mechanisms in pancreatic cancer organoids under KRASG12D inhibition via pooled CRISPR-Cas9 druggable library screen (AACR 2026) - "By scaling a druggable lentiviral based CRISPR-Cas9 screen, we show potential signaling pathways that aid in resistance to tool compound MRTX in PDAC organoids. Thus, addressing the unmet need of predictive resistance modeling in PDAC organoids. Further work includes selective knockout of key targets to confirm synthetic lethality with MRTX1133."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN1B • IL6 • KRAS • UQCRC1

EV-based delivery of chemically modified siRNA achieves MRTX1133-comparable efficacy in KRAS G12D-mutant pancreatic cancer (AACR 2026) - "Shock wave-engineered EV delivery overcomes the major barriers of RNA therapeutics in PDAC. EV-siRNA #41 demonstrates potent, selective, and durable antitumor activity at microdose levels and outperforms both LNPs and a leading KRAS G12D inhibitor. These data position EV-siRNA #41 as a first-in-class, mutation-specific RNA therapeutic ready for IND-enabling development."

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

Combining RAS inhibitors with the clinical RNR inhibitor BBI-825 to prevent the emergence of extrachromosomal DNA (ecDNA)-driven resistance to RAS-targeted therapies in colorectal cancer (AACR 2026) - "RAS inhibitors used were MRTX1133 and zoldonrasib (KRASG12D), sotorasib and adagrasib (KRASG12C) and daraxonrasib. We show in multiple models of MSS CRC that the selective RNR inhibitor BBI-825 combined with RAS inhibitors delayed or prevented RAS targeted therapy-acquired resistance in a novel approach that subverts the emergence of resistance. The selective sensitivity of MSS CRC models, particularly those that harbor ecDNA, further supports the distinct mechanism of action of BBI-825 and this potential new and important strategy to improve RAS inhibitor efficacy."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • KRAS • MYC

Defining a molecular signature for KEAP1-NRF2 mediated resistance to KRAS inhibition in KRAS-mutant pancreatic and lung cancer (AACR 2026) - "We determined that loss of KEAP1 and activation of the transcription factor NRF2 drove resistance to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977...This signature was also distinct from transcriptional changes associated with other mechanisms driving KRAS inhibitor resistance (ERK, MYC, and YAP/TAZ-TEAD). Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the clinical candidate glutamine antagonist DRP-104 (sirpiglenastat) strongly enhanced KRAS inhibitor-mediated growth suppression in KRAS-mutant PDAC and NSCLC tumors in vivo. In summary, our studies established a gene signature for KEAP1 loss-driven resistance and validated a therapeutic strategy to overcome KEAP1-NRF2-driven RAS inhibitor resistance."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KEAP1 • KRAS

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation (AACR 2026) - "In the resistant models, disrupting VEGFA-VEGFR2 signaling using KDR knock-out and ramucirumab treatment restored MRTX1133 sensitivity and reversed EMT in resistant cells. Inhibition of hyperactivated PI3Kγ using eganelisib, a selective p110γ inhibitor, also replicated the same results...In a mouse xenograft model of MRTX1133-resistant PANC-1 cells, anti-VEGFR2 antibody (DC101) treatment combined with MRTX1133 rechallenge more effectively reduced tumor growth and angiogenesis than either agent alone, without significant changes in body weight...Importantly, co-targeting this axis with VEGFR2 or PI3Kγ inhibitor restored sensitivity to KRAS inhibition. These findings provide a rationale for further biomarker-guided clinical trials of combined VEGFA-VEGFR2 and KRAS inhibition in patients experiencing acquired resistance after KRAS inhibitor treatment."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KDR • KRAS • PIK3CG

MRTX1133 suppresses ERK signaling but elicits context-dependent antiproliferative responses in KRAS (G12C) cancer cells. (PubMed, Mol Cancer Ther) - "Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This appears to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms."

Journal • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • RPS6

Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders. (PubMed, Front Cell Dev Biol) - "While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRASG12C (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRASG12D (such as Mirati's MRTX1133), has shown promise. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the in vitro delivery of KRASG12C mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity."

Biomarker • Journal • Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • HRAS • KRAS • MMP2 • MMP9 • NRAS

Screening of kinase inhibitors in the triple negative KRAS G13D-mutated MDA-MB-231 breast cancer cell line. (PubMed, Sci Rep) - No abstract available

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KRAS

Pharmaco-genomic characterization of pancreatic and biliary tract cancer tumoroids for drug response. (PubMed, iScience) - "Notably, combining a G9a degrader (G9D-4) with the KRASG12D inhibitor MRTX1133 elicited synergistic anti-tumor effects in KRASG12D-mutant tumoroids. Overall, our study provides preclinical insights from a small PDAC and BTC tumoroid cohort, supporting tumoroid-based platforms for exploratory drug screening and pharmacogenomic analyses and suggesting potential therapeutic directions that warrant further validation."

Journal • Biliary Cancer • Biliary Tract Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PIK3CA

Combination of PARP and KRASG12D inhibitors enhances therapeutic efficacy by exploiting vulnerabilities in PDAC. (PubMed, Nat Commun) - "Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8+ T-cell infiltration. These findings demonstrate that co-targeting KRASG12D and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRASG12D-driven PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRCA1 • CD8 • KRAS • RAD51 • RPA2

FGTI-2734 prevents ERK-mediated resistance and enhances MRTX1133 efficacy in KRAS G12D pancreatic cancer. (PubMed, Eur J Cancer) - "These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • CDKN2A • KRAS • PI3K • SMAD4 • TP53

Discovery of KRAS-G12D degraders via exploration of various E3 ligases. (PubMed, Eur J Med Chem) - "In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133...In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders."

Journal • Targeted Protein Degradation • CRBN • KRAS

Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations (Nature) - "We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS."

Preclinical • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Computational repurposing of approved drugs targeting KRAS G12D and EGFR for colorectal cancer therapy. (PubMed, PLoS One) - "This in silico study predicts Carteolol as a potential dual-targeting therapeutic agent, requiring biochemical and cellular validation before clinical relevance can be established."

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