RMC-7977 / Revolution Medicines - LARVOL DELTA

Direct small molecule inhibition of RAS enhances JAK2 inhibitor therapy in preclinical models of myeloproliferative neoplasms (ASH 2025) - "While the MEK inhibitor binimetinib readily suppressed pERK levels, its GI50 was > 5μM in these cells, suggesting direct inhibition of RAS may more efficiently suppress signaling requisite forJAK2-driven growth. RMC-7977 treatment suppressed inflammatorycytokine levels including TNFα and IL-6, two cytokines implicated in MPN pathogenesis, among others.Importantly, treatment of healthy mice concurrently with RMC-7977 and ruxolitinib was well tolerated asevidenced by the absence of impact on hematologic parameters and body weight. Our results reveal thatdirect inhibition of RAS and JAK2 may represent a promising therapeutic strategy for MPN patients andprovide evidence RAS inhibition has potential beyond solid tumor indications."

Preclinical • Aplastic Anemia • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Solid Tumor • Thrombocytosis • CALR • DUSP6 • IL6 • KRAS • TNFA

Human HSPCs CRISPR-engineered to endogenously express oncogenic NRAS generate a transplantable lethal myeloid malignancy targetable with novel RAS therapeutics (ASH 2025) - "Here, we established a model of endogenous NRASG12D in human HSPCs and showed thattransplantation of such engineered cells into mice leads to a lethal myeloid neoplasm with prolongedlatency compared to our UBC-NRASG12D model. We extended this model to other oncogenic NRASmutations and demonstrated that the pan-RAS inhibitor RMC-7977 treatment reduces their proliferationand replating potential, while having little effect on NRAS-wildtype cells. Thus, both exogenous andendogenous oncogenic NRAS expression in human HSPCs leads to engraftment and development ofmyeloid malignancy with features of primary human disease."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD33 • CD34 • NRAS • RAS

RAS G12 and Q61 codon mutations confer distinct disease characteristics in Acute Myeloid Leukemia and exhibit differential response to RAS(ON) inhibitor RMC-7977. (ASH 2025) - "There is growing interest in understanding and targeting RASmutations in AML, owing to studies indicating that RAS mutations are associated with relapse aftermultiple novel targeted therapy agents, including azacitidine/venetoclax, and FLT3 and IDH1/2 inhibitors.In addition, the advent of novel RAS(ON) inhibitors showing promise in solid cancers offers a therapeuticstrategy that could be deployed to target these mutations. Our group has previously described the use oftamoxifen inducible, Cre-recombinant single- and double-mutant mouse models harboring Npm1c,NrasG12D, and NrasQ61R mutant alleles and shown that there are distinct codon specific phenotypedifferences in RAS-mutant AML...RMC-7977 was shown to ablate MAPK signaling and have high potency across a range of RAS-mutated AML cell lines, with highest potency observed in THP1 (G12D, IC50 585pM), compared to OCI-AML3 (Q61L, IC50 5.85pM) and HL60 (Q61L, IC50 2.78nM). RMC-7977 induced a variable degree ofapoptosis and..."

Acute Myelogenous Leukemia • Developmental Disorders • Hematological Malignancies • Leukemia • Solid Tumor • Thrombocytopenia • ANXA5 • FLT3 • GLI2 • IDH1 • IDH2 • NRAS

Exploiting RAS pathway addiction as a therapeutic vulnerability in myeloid sarcoma (ASH 2025) - "To investigate the role of RAS activation in myeloid sarcoma, we lentivirally transduced human CD34+cord blood cells to express myeloid driver mutations SRSF2P95H, ASXL1del1900-1922 and a doxycycline(Dox)-induced NRASG12D and transplanted them into NSGS mice. To exploretherapeutic targeting of RAS signaling, we used a Tet2-/-/NrasG12D bone marrow transplant model inRag2-/-Il2rg-/- mice, treating them with the pan-RAS inhibitor RMC-7977 starting 5 days after transplant.While vehicle-treated mice developed extramedullary tumors and succumbed within 3 weeks, RMC-7977-treated mice had significantly reduced extramedullary tumor burden and extended overall survival. Insummary, our findings underscore the critical role of RAS pathway activation in myeloid sarcomadevelopment and demonstrate that targeting RAS signaling could be a promising therapeutic strategy foraffected patients."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • CNS Disorders • Hematological Malignancies • Leukemia • Psychiatry • Sarcoma • Solid Tumor • ASXL1 • B2M • CD34 • CD8 • DUSP2 • IL2RG • KRAS • MAPK1 • NRAS • PTPN11 • SNAI2 • SRSF2 • TET2

PAN-RAS INHIBITION AS A NOVEL THERAPEUTIC STRATEGY FOR RAS-DRIVEN RHABDOMYOSARCOMA (CTOS 2025) - P1/2, P3 | "RMC-6236 and its tool compound RMC-7977 are novel state selective pan-RAS inhibitors that inhibit GTP-bound oncogenic and wild-type (WT) RAS, known as RAS(ON)i. Our data demonstrate that RAS(ON)i decreases RAS-MEK-ERK signaling, prevents adaptive PI3K-AKT signaling, and decreases in vitro and in vivo tumor growth in RAS-driven RMS. These findings can rapidly translate into a clinical trial for patients with RAS-pathway-altered RMS using clinically available compounds in late-stage clinical development."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HRAS • KRAS • Myogenin • NRAS

CRISPR-Cas9 Screening Identifies Resistance Mechanisms to KRAS Inhibition in Pancreatic Cancer. (PubMed, Cancer Res) - "Further, EGFR inhibitor erlotinib synergized with the RAS(ON) multi-selective inhibitor RMC-7977 in KRASQ61H-mutant PDAC cell lines and in cell lines with highly active EGFR by mitigating ERK rebound activity. KRASi-resistant cell lines featured sustained ERK/MAPK dependence despite decreased ERK activity. Together, these findings enhance the understanding of intrinsic and acquired resistance to KRASi and identify therapeutic vulnerabilities that can potentially be exploited for KRASi combination therapies in pancreatic cancer patients."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • PIK3CA • PIK3CG

Preclinical Activity of RAS(ON) Multi-Selective Inhibitor RMC-7977 and Therapeutic Combinations in AML with Signaling Mutations (ASH 2024) - "RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS (RAS(ON) multi-selective) and is a preclinical tool compound representative of the investigational drug RMC-6236...Mice receiving vehicle, venetoclax or gilteritinib had an average residual leukemic burden of 88.9% (SD=±23.3), 98.9% (SD=±0.4), and 79.7% (SD=±5.3) respectively, while those receiving RMC-7977 or RMC-7977 + venetoclax exhibited 46.12% (SD=±23.9) and 44.27% (SD=±15.8), respectively...Our data suggest that RAS(ON) multi-selective inhibition is an effective therapeutic approach to overcome RAS/MAPK-mediated resistance to FLT3i and is active in AML driven by oncogenic RAS mutations, addressing limitations of current standard of care treatments for AML with signaling mutations. These results provide a strong preclinical rationale for the clinical investigation of RAS(ON) multi-selective inhibition in FLT3- and RAS- mutant AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • IDH1 • IDH2 • KMT2A • KRAS • NRAS • PTPRC

RASMULTI(ON) Inhibitor RMC-7977 Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 Inhibitors in AML Models (ASH 2023) - P1/2 | "RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need."

IO biomarker • Acute Myelogenous Leukemia • Oncology • CASP3 • CASP7 • FLT3 • IDH1 • IDH2 • KIT • KRAS • NRAS

Pan-RAS Inhibitor RMC-7977 Overcomes Oncogenic RAS Signaling and Exerts Antileukemic Effects in CMML/AML Cells (ASH 2024) - "FDA-approved KRASG12C inhibitors sotorasib and adagrasib demonstrate significant clinical response for non-small cell lung cancer patients harboring KRAS G12C mutation, and early data suggests that pan-RAS inhibitors are safe and effective in PDAC and NSCLC. Experiments evaluating the effects of RMC-7977 in cell line xenografts and additional patients' primary samples are ongoing and will be presented.Collectively, we have demonstrated that the pan-RAS inhibitor RCM-7977 is highly effective against RAS mutated CMML/AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions."

IO biomarker • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • CD34 • FLT3 • HRAS • IDH1 • IDH2 • JAK2 • KIT • KRAS • NRAS

RAS(ON) multi-selective inhibition drives antitumor immunity in preclinical models of NRAS-mutant melanoma. (PubMed, Cancer Immunol Res) - "Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Consistent with these preclinical data, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib in an ongoing Phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multi-selective inhibitors for the treatment of NRAS-mutant melanoma."

IO biomarker • Journal • Preclinical • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • NRAS • PD-L1

Dual MAPK/VEGF inhibition for KRAS-mutated brain arteriovenous malformations. (PubMed, J Neurosurg) - "Our findings suggest that, in addition to promoting bAVM formation, KRAS mutations in cerebral endothelial cells might be causally implicated in bAVM rupture. Additionally, concomitant inhibition of the MAPK and VEGF pathways could be a promising novel therapeutic strategy for KRAS-mutated bAVMs."

Journal • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • KRAS

Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML. (PubMed, Blood) - "In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Pan-RAS inhibition as a novel therapeutic strategy in RAS-driven rhabdomyosarcoma (AACR-NCI-EORTC 2025) - "RMC-6236 (and the related tool compound RMC-7977) are novel state-selective pan-RAS inhibitors that inhibit both GTP-bound oncogenic and wild-type (WT) RAS, known as RAS(ON)i. The efficacy of RAS(ON)i is enhanced with concurrent PI3K-AKT inhibition. These findings have the potential to rapidly translate into a clinical trial for patients with RAS-pathway-addicted RMS using clinically available compounds in late-stage clinical development."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HRAS • KRAS • Myogenin • NRAS

RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wildtype RAS Activation in Non-Small Cell Lung Cancer. (PubMed, Cancer Res) - "Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials...Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors, RMC-4998 and RMC-7977...Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependance, and acquired reliance on cell cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in combination with other therapies."

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

Fibroblast STAT3 Activation Drives Organ-Specific Premetastatic Niche Formation. (PubMed, Cancer Res) - "Inactivating oncogenic KRAS reduced serum IL6 and reverted fibroblast STAT3 phosphorylation in mouse lungs; loss of lung fibroblast STAT3 phosphorylation was similarly observed when mice were treated with the pan-RAS inhibitor RMC7977...In human metastasis samples, phosphorylated STAT3 in fibroblasts was similarly more abundant in the lungs than liver. Together, these data point to organ-specific mechanisms driving formation of the PMN and indicate that reprogramming of the microenvironment prior to metastasis might support early dissemination of pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • STAT3

Mapping and modulating epithelial-mesenchymal plasticity under RAS(ON) multi-selective inhibition in PDAC through lineage tracing and Perturb-seq Free (AACRPanCa 2025) - "To comprehensively map and modulate epithelial-mesenchymal (E-M) cell state plasticity in response to KRASi treatment, we performed CRISPRi Perturb-seq (single-cell gene expression readout) with lineage tracing on a patient-derived PDAC cell line treated with the RAS(ON) multi-selective inhibitor RMC-7977...Notably, we identified several TFs, displaying KRASi-dependent changes in state transition dynamics, either promoting (ELF3, MEIS2 among others) or decreasing (ZNF281, IRF9, among others) probabilities of M→E transitions when compared to non-targeting controls. These preclinical findings suggest that perturbation of these factors may be used as a paradigm to prevent cell state plasticity upon acute KRASi treatment and could be used to homogenize tumor populations towards a treatment-sensitive state."

Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ELF3 • KRAS

RAS(ON) multi-selective inhibition remodels cancer-associated fibroblast subtypes and extracellular matrix in pancreatic cancer Free (AACRPanCa 2025) - "While RAS(ON) multi-selective inhibitors like the investigational agent daraxonrasib (RMC-6236) and the related preclinical tool compound RMC-7977 are designed to target the KRAS-mutant malignant epithelium, their effects on the surrounding tumor stroma remain underexplored. These preclinical findings suggest that systemic pan-RAS-GTP inhibition alters not only the malignant epithelium but also the broader PDAC architecture through effects on stromal components. Understanding these stromal adaptations will enable improved assessment of tumor behavior and the development of more effective combination therapies."

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

pan-RAS-GTP inhibition relieves angiosuppression in PDAC by repressing Hedgehog paracrine signaling Free (AACRPanCa 2025) - "We previously showed that RMC-7977, a preclinical RAS(ON)-multi inhibitor related to the investigational agent daraxonrasib, shows strong preclinical efficacy at clinically-relevant, tolerable doses...Mechanistic studies confirm that RAS inhibition downregulates the hedgehog-driven paracrine cascade that enforces angiosuppression. In ongoing work, we are now examining whether the increased vasculature leads to increased perfusion and drug delivery, as anticipated."

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

Ex-vivo organotypic tumor model of metastatic core biopsy serve as a pragmatic platform for real-time personalized therapy in pancreatic adenocarcinoma Free (AACRPanCa 2025) - "Based on individual patient's known prior sensitivity to first or second-line chemotherapy, we tested a range of chemotherapeutic treatments (e.g. FOLFIRINOX, gemcitabine/paclitaxel) and targeted agents (e.g. pan-RAS inhibitor RMC-7977 and MEK inhibitor trametinib) against negative control (DMSO)...Our organotypic tumor culture system using patient-derived core biopsies represents a novel and pragmatic approach to real-time personalized therapy in metastatic PDAC. While it relies on presumed homogeneity of tissue across the core biopsy, this system is cost-effective, does not rely on take rate (as in organoids or xenograft models), and allows for preliminary viability readouts within days of biopsy. Further work is ongoing to validate viability signals with protein signals in fixed tissue, as well as comparisons to matured patient outcome and treatment data."

Biopsy • Metastases • Preclinical • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • CA 19-9 • CASP3 • KRAS • PTPRC

EMT-associated integrin signaling drives resistance to RAS-GTP inhibition in pancreatic cancer Free (AACRPanCa 2025) - "Critically, inhibition of integrin signaling components, including integrins, FAK, and PAK, restored sensitivity to RMC-7977 in vitro. Collectively, our preclinical results highlight integrin-mediated signaling as a key driver of EMT-associated RAS independence and implicate the potential of targeting this axis to overcome resistance to RAS inhibition in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

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

Pan-RAS Inhibitor RMC-6236 Suppresses Myeloma Growth and Shows Enhanced Efficacy with SWI/SNF Inhibition (IMS 2025) - " We evaluated the anti-myeloma activity of novel pan-RAS inhibitors, RMC-6236 and RMC-7977, across a broad panel of over 50 MM cell lines. Our findings demonstrate that RMC-6236 shows broad and potent anti-tumor activity in RAS- and FGFR3-driven MM by suppressing MAPK and mTORC1 signaling. Its therapeutic efficacy is significantly enhanced in combination with SWI/SNF inhibitor FHD-286. These findings represent a promising therapeutic strategy that supports further clinical investigation in RAS-dependent MM."

Clinical • Hematological Malignancies • Multiple Myeloma • EIF4EBP1 • FGFR3 • KRAS • MAPK1 • NRAS • RPS6 • RPS6KA3 • SLC3A2

Genetic mechanisms of resistance to targeted KRAS inhibition. (PubMed, bioRxiv) - "Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), RAS(ON) G12C-selective tri-complex inhibitor (RMC-4998), and RAS(ON) multi-selective tri-complex inhibitor (RMC-7977). Notably, we identify a recurrent missense mutation in capicua ( Cic ), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NFκB signaling in CIC-mutant cells can resensitize them to RAS pathway inhibition and overcome resistance."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Modelling Acral Melanoma in Admixed Brazilians Uncovers Genomic Drivers and Targetable Pathways. (PubMed, medRxiv) - "Notably, the pan-RAS(ON) inhibitor RMC-7977 effectively reduced viability in NRAS -, KRAS -, and KIT -mutant AM cell lines. Finally, CRISPR screens revealed dependencies selectively essential in AM, including CRKL and SF3B4 , highlighting previously unrecognized vulnerabilities. Our findings emphasize the distinct biology of AM compared to other subtypes of melanoma, provide a valuable resource of models reflective of Latin American ancestry, and identify potential drivers and therapeutic targets."

Journal • Tumor mutational burden • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • ATM • CCND1 • CDK4 • CHEK1 • CRKL • KRAS • NRAS • TMB