RMC-7977 / Revolution Medicines - LARVOL DELTA

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

Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance. (PubMed, bioRxiv) - "We propose that concurrent treatment with ONC201 may delay onset of resistance to RAS inhibitor therapy. ClpP activation by dordaviprone/ONC201 suppressed PDAC cell growth and overcame resistance to the RAS(ON) multi-selective inhibitor RMC-7977, providing support for investigating this combination as a potential combination treatment for KRAS-mutant pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KEAP1 • KRAS

Understanding the Kinetic Mechanism of Ligands Stabilizing the RAS-CYPA Interaction. (PubMed, J Chem Inf Model) - "Moreover, the results also uncover the dynamic process of stabilizer-mediated KRAS-CYPA stabilization and the mechanistic origin of the binding selectivity. This study provides essential molecular-level insights into RMC7977's function and offers a valuable computational framework for evaluating the stabilization effect of ligands targeting the KRAS-CYPA and other challenging PPI systems."

Journal • Oncology • Targeted Protein Degradation • KRAS • RAS

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. (PubMed, Nature) - P1 | "Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985)."

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

Broad-Spectrum RAS Inhibition in Pancreatic Ductal Adenocarcinoma: Mechanistic Advances and Therapeutic Promise. (PubMed, Pharmaceuticals (Basel)) - "Recent advances in mutation-specific inhibitors (e.g., sotorasib for KRASG12C) have demonstrated clinical efficacy but face limitations in tumor types like PDAC, where KRASG12C mutations are rare. Broad-spectrum pan-RAS inhibitors (e.g., RMC-7977, RMC-6236, ADT-007/ADT-1004) now offer promise by targeting active GTP-bound or nucleotide-free RAS across isoforms and mutations...Challenges remain in achieving a therapeutic index due to RAS's role in normal tissue homeostasis, but tumor-specific drug accumulation and rapid normal tissue recovery may mitigate risks. Ongoing trials are evaluating combination strategies with immunotherapy and chemotherapy, positioning pan-RAS inhibitors as transformative agents for RAS-driven cancers."

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

Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma. (PubMed, bioRxiv) - "Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that, in partnership with cyclophilin-A (CYPA), inhibit RAS[GTP] signaling...Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • BRAF • MAP2K1 • NRAS

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