MRTX1133 / BMS - LARVOL DELTA

A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models (AACR 2025) - "We found that KRAS G12D inhibitor (MRTX1133) in combination with AOH1996 enhanced cytotoxicity in several PDAC cell lines at lower MRTX1133 concentrations, potentially reducing toxic side effects. We also observed enhanced efficacy of the chemotherapeutic agent oxaliplatin, which is a platinum compound in the FOLFIRINOX regimen, in combination with AOH1996. Collectively, our results show that AOH1996 is a promising agent for PDAC treatment which potentiates chemotherapy, and targeted KRAS G12D inhibitors. In vivo xenograft studies combining AOH1996 and KRAS inhibitors are ongoing."

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

Targeting XPO1 to enhance the durability of response of MRTX1133 in pancreatic ductal adenocarcinoma (AACR 2025) - "This is the first study showing that KPT8602 treatment can overcome resistance to MRTX1133 and synergistically augment the antitumor effects of MRTX1133 in PDAC preclinical models. This combination regimen can potentially prevent or delay drug resistance by making it feasible to achieve a more durable response at a lower dose of KRASG12D inhibitor."

IO biomarker • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCND1 • DUSP6 • EIF4EBP1 • KRAS • mTOR

Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with KRAS G12D (AACR 2025) - "Although no phosphorylation of receptor tyrosine kinases that could be combination drug candidates were observed, several MEK inhibitors, such as trametinib, selumetinib and binmetinib, enhanced the efficacy of MRTX1133 in cell viability assays. The combination of trametinib with MRTX1133 suppressed tumor growth compared to MRTX1133 monotherapy with tolerable toxicity in KRAS G12D-mutated NSCLC in vivo models. In conclusion, our findings indicate that the preclinical efficacy of MRTX1133 monotherapy was limited for NSCLC with KRAS G12D, and therapeutic potential of MEK inhibitors in combination with MRTX1133."

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

Profiling Ras inhibitors for effects on GTP hydrolysis using the Transcreener GDP assay (AACR 2025) - "MRTX1133, which binds noncovalently to GDP-bound KRas G12D, inhibited the G12D mutant with an IC50 of 8.4 nM, and was less potent with the G12V and WT enzymes; IC50 = 48 nM and 69 nM, respectively. We note that these GTPase assays require nanomolar concentrations of protein, and therefore cannot be used to accurately determine the potency of covalent inhibitors, such as sotorasib, that bind with picomolar affinity. However, for non-covalent inhibitors, such as MRTX1113 and BI-2865, measuring GTPase activity is a robust approach for selectivity profiling and may yield mechanistic insights different from those gleaned from guanine nucleotide binding/release assays or biophysical methods, e.g. SPR."

Oncology • KRAS

The KRASG12Dinhibitor MRTX1133 demonstrates significant antitumor activity and enhances nanoparticle-paclitaxel chemotherapy outcomes in pancreatic cancer (AACR 2025) - "The combination of nab-paclitaxel and gemcitabine (NPT-GEM) represents the standard treatment for advanced and metastatic PDAC, yielding a median survival of approximately 8.5 months. These findings highlight the significant therapeutic potential of MRTX1133, particularly in combination with standard chemotherapy, for the clinical management of KRASG12D-mutant PDAC patients."

Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP3 • CDKN2A • KRAS • MIA • SMAD4 • TP53

A precision polypharmacology approach to co-target EGFR and PI3 kinase: the power of structure-based drug design to generate therapeutic agents with versatility in multiple combination settings (AACR 2025) - "In vivo studies were carried out in KRAS G12D mutant tumor-bearing mice showing that treatment with MTX-531 led to striking enhancement of KRAS inhibitor (MRTX-1133) activity against a broad spectrum of gastrointestinal cancers (pancreatic, colorectal, gastric) as evidenced by a high incidence of durable tumor regressions. Collectively, these studies demonstrate the versatility of MTX-531 to serve as the backbone of combination regimens across diverse modalities encompassing treatment with targeted therapies, radiation, or immune checkpoint inhibitors. Based on its promising preclinical profile, MTX-531 represents a first-in-class approach to precision polypharmacology that demonstrates the power of rational structure-based drug design to target multiple resistance drivers in a single molecule."

IO biomarker • Breast Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • EGFR • KRAS

Optimization of CRISPR-Cas9 library screens in pancreatic cancer organoid models targeting KRASG12D (AACR 2025) - "Here, we optimize a CRISPR-Cas9 lentivirus screen in 3D patient-derived cancer organoids (PCOs) to study resistance mechanisms and guide combination therapy using the KRASG12D inhibitor MRTX1133. PDAC PCOs were derived from surgical specimens... Here, we demonstrate the optimization of CRISPR-Cas9 screening with 3D PDAC PCOs using ddPCR to validate the efficiency of transfection. Importantly, the degree of puro selection and lentivirus transfection did confer multiplicity in viral transfections. The ongoing work is aimed at understanding the time course dynamics of gene editing between early (14 day) and late (28 day) resistance to KRASG12D inhibition using the Model-based Analysis of the Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method."

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

Integrative analysis of acquired drug resistance to KRAS(G12D) inhibitors (AACR 2025) - "Novel therapeutic approaches such as RAS(ON) inhibitors like RMC-6236 or specific KRAS(G12D) PROTAC degraders can significantly inhibit cell proliferation in vitro not only in MRTX1133 acquired resistance but also in adagrasib resistance models. Complex transcriptomic reorganization shows the upregulation of CD24 -a potential cancer stem cell related gene- and the epithelial to mesenchymal signature highlight the difficulty to target drug resistant cells. These findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • CD24 • HRAS • KRAS • NRAS

KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC (AACR 2025) - "Moreover, other relevant therapies for PDAC such as gemcitabine and Oxaliplatin showed no significant difference between our models. Validating this using an in vivo orthotopic model, MRTX1133 induced profound tumor regression solely in the wild-type group compared to the HuR-KO cohort...combined with ongoing studies, we highlight a significant breakthrough in the understanding of PDAC cells addiction to Kras signaling in the context of the pro-oncogenic HuR molecule, revealing that the absence of HuR confers resistance to KRAS inhibitor drugs. Understanding the interplay between KRAS and HuR could offer a novel strategy to disrupt the oncogenic KRAS signaling cascade and overcome the potential inherent and acquired resistance mechanisms of KRAS-mutant PDACs to promising, KRAS-targeted therapies."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • ELAVL1 • KRAS

Targeting KRAS selectively induce metabolic reprogramming in pancreatic cancer (AACR 2025) - "Specifically, while KRAS/MAPK inhibition using drugs such as MRTX1133 and Trametinib suppresses growth in some cell lines, the same treatment induces or does not alter the growth of other cell lines, and selectively impacted cell migration. Our study reveals context-dependent response to KRAS inhibition in PDAC and suggests targeting nutrient transporters to overcome therapeutic resistance. Laiba Shiekh and Matthew Cheung contributed equally to this work."

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

A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance (AACR 2025) - "Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • EGF • KRAS

GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models (AACR 2025) - P1/2 | "Furthermore, GFH375 was more potent than other KRAS G12D inhibitors (e.g. RMC-9805, MRTX1133) in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in MEFs expressing human KRAS G12D...Combination with the RAF/MEK clamp avutometinib also enhanced the anti-tumor efficacy of GFH375...Altogether, GFH375 is a potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab. These results support the ongoing clinical evaluation of GFH375 for treatment of patients with KRAS G12D mutant cancers (NCT06500676)."

Combination therapy • Preclinical • Colorectal Cancer • Endometrial Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Adaptive rewiring after prolonged KRAS inhibition sensitizes PDAC cells to sequential targeting with ferroptosis inducers (AACR 2025) - "A drug screen on primary PDAC cell lines derived from the model that were resistant to KRASG12D inhibition identified a strong RSL3-induced ferroptosis sensitivity of KrasG12D-depleted cell lines compared to their KrasG12D-proficient counterpart. Inhibitors MRTX1133 and RMC-6236 also conferred ferroptosis sensitization in various mouse and human PDAC cell lines...These, together with global changes in transcriptome, suggest that multiple pathways likely contribute to ferroptosis sensitization, including KEAP-NRF2 redox balance pathway, iron and lipid metabolism, and also hint at involvement of TGFβ-EMT signaling axis. Our results suggest that a sequential two-hit therapeutic approach with KRAS inhibition followed by subsequent ferroptosis induction could efficiently mitigate resistance to KRAS-inhibitor based therapies in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KEAP1 • KRAS • MAP3K7 • SLC7A11

IBI3019, a first-in-class EGFR/CDH17/CD16A tri-specific antibody, demonstrated potent efficacy against CRC and an excellent safety profile in preclinical studies (AACR 2025) - "Inhibition of EGFR signaling is clinically effective in colorectal cancer (CRC) as evidenced by the approval for Cetuximab in combination with chemotherapy or Encorafenib, a BRAF inhibitor, and the promising clinical results when combined with KRAS inhibitors, such as Adagrasib or Sotorasib...Additionally, IBI3019 incorporates a high affinity CD16A single domain antibody that mediates stronger antibody-dependent cell cytotoxicity (ADCC) than IgG1 used in Cetuximab or the low fucosylated Fc of Amivantamab, a bispecific antibody targeting c-MET and EGFR, both in vitro and in vivo...It exhibited strong synergy with Fulzerasib, a KRAS G12C inhibitor and MRTX1133, a KRAS-G12D inhibitor...IBI3019 is a highly optimized FIC molecule with enhanced EGFR blocking capability and ADCC, maximizing tumor inhibition while minimizing toxicity. Its superior efficacy and safety profile support further clinical evaluation."

Preclinical • Trispecific • Colorectal Cancer • Oncology • Solid Tumor • CDH17 • FCGR3A • KRAS • MET

Targeting KRAS in appendiceal cancer: promising results with MRTX1133 and RMC-6236 in organoids and PDX models (AACR 2025) - "Single-agent MRTX1133 was highly potent and specific to KRASG12D AA tumors, whereas pan-RAS inhibitor RMC-6236 inhibited both KRASG12D and KRASG12V organoids at nanomolar concentrations. MRTX1133 demonstrated robust suppression of the RAS-MEK-ERK pathway and prolonged survival in vivo models of AA."

Appendix Cancer • Oncology • CASP3 • CASP7 • KRAS

Exploiting the spontaneous intrahepatic cholangiocarcinoma mouse models to uncover MRTX1133's dual role in directly inhibiting KRASG12D-driven tumor progression and modulating the immune landscape (AACR 2025) - "This study is the first to validate the oncogenic role and therapeutic vulnerability of the KRASG12D mutation in iCCA. It also suggests the potential benefits of combining KRASG12D inhibitor MRTX1133 with ICB immunotherapy with synergistic effects."

IO biomarker • Preclinical • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CD8 • KRAS • NICD

The effects of MRTX1133 on antitumor immunity in KRASG12D-mutant lung cancer (AACR 2025) - "KRASG12D-mutant lung tumors in mice exhibited T cell exhaustion. MRTX1133 showed therapeutic efficacy in the preclinical KRASG12D-mutant lung cancer model, possibly by enhancing antitumor immune responses along with oncogenic signaling inhibition. In human KRASG12D-mutant lung cancer cell lines, MRTX1133 reduced cell proliferation and increased antitumor cytokine expression, especially in SK-LU-1 cells."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCL20 • CD4 • CD8 • HAVCR2 • IFNG • KRAS • LAG3 • PD-1 • PD-L1 • TIGIT

Physiologic epidermal growth factor modeling improves sensitivity of KRASG12Dinhibitor MRTX1133 (AACR 2025) - "Physiologic EGF stimulation yielded improved sensitivity to MRTX1133 in a manner independent of organoid growth rate. While resistance to MRTX1133 can be observed in organoid models, understanding this as a function of accurate EGF stimulation remains a critical need particularly at informing relevant resistance mechanisms. Future work includes evaluating this across a diversity of KRASG12D cancer models and comparing physiologic EGF across therapeutic screening applications in combination."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

MUC1-C is a target for antibody-drug conjugate treatment of MRTX1133-resistant KRAS G12D mutant pancreatic ductal adenocarcinomas (AACR 2025) - "These findings indicate that MUC1-C confers resistance of PDAC KRAS G12D mutant cells to MRTX1133 and identify MUC1-C as a target for ADC treatment of patients refractory to MRTX1133 treatment."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • EGFR • GSDME • KRAS • MUC1 • ZEB1

Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids (AACR 2025) - "As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS...In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy."

Oncology • Solid Tumor • KRAS • PIK3CA

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

Selective inhibition of NRAS-GTP in cancer models with small molecule NEOS-223 (AACR 2025) - "NEOS-223 has a greater synergistic effect on inhibition of cell proliferation combined with specific targeted inhibitors such as gefitinib (EGFR), sotorasib (KRAS G12C), vemurafenib (BRAF V600E) and MRTX1133 (KRAS G12D) correlating with stronger suppression of EGFR-RAS-MAPK signaling. Our study highlights the feasibility of developing NRAS selective inhibitor for therapeutic efforts and these results suggest that NRAS plus KRAS to be a promising strategy for treating both EGFR and RAS mutant tumors. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting NRAS mutant, dependent and resistance tumors."

Preclinical • Colon Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • HRAS • KRAS • NRAS

Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors (AACR 2025) - P1 | "In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models.We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response."

Preclinical • Oncology • Solid Tumor • KRAS

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

Combination of MTA-cooperative PRMT5 inhibitor BMS-986504 and KRAS inhibitors for the treatment of MTAP-deleted KRAS-mutant pancreatic cancer (AACR 2025) - "We validated co-targeting KRAS as a combination strategy and found that combined small molecule inhibition of PRMT5 and G12C/D-mutant KRAS (using adagrasib and MRTX1133, respectively) effectively suppressed MTAP-del PDAC growth in vitro and in vivo. Further, we determined that, while PRMT5 and KRAS regulate distinct transcriptomes, they converge on common pathways governing cancer cell growth and combined inhibition of PRMT5 and KRAS caused marked downregulation of PDAC-essential genes. These findings provide a rationale for combined inhibition of PRMT5 and KRAS to maximize targeted therapies for MTAP-del and KRAS-mutant biomarker-positive PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MIA • MTAP • PRMT5