RMC-7977 / Revolution Medicines - LARVOL DELTA

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

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

Distinct ERK and PI3K dependencies mediate a heterogeneous response to RAS(ON) inhibition in KRAS-mutant colorectal cancer. (PubMed, Cell Rep) - "Here, we evaluate RMC-7977, a RAS(ON) multi-selective inhibitor, which shows a heterogeneous response in a panel of preclinical CRC models...However, in tumors with strongly ERK-dependent cyclin D1, vertical inhibition of RAS and MEK prevents feedback re-activation of the MAPK/ERK pathway and is more effective. In summary, we identify cyclin D1 as an important integrator and functional readout of upstream signaling that can inform optimal combination strategies for KRAS-mutant CRC."

Heterogeneity • Journal • Colorectal Cancer • Oncology • Solid Tumor • CCND1 • KRAS

Vertical RAS(ON) and MEK blockade Prevents ERK Reactivation and Induces Durable Tumor Control in NF1-Associated Peripheral Nerve Tumors (EACR 2026) - "MPNSTs are also largely refractory to MEK inhibition and have no approved targeted therapeutic option.Material and PN and MPNST cell models were treated with MEK inhibitors alone or combined with inhibitors of different nodes of the MAPK pathway, including the clinical-stage multi-selective RAS(ON) inhibitor RMC-6236 (or its preclinical analogue RMC-7977). Adaptive ERK reactivation represents a central non-genetic resistance mechanism in NF1-associated tumors. Vertical MAPK pathway blockade with combined RAS(ON) and MEK inhibition suppresses signaling plasticity and enables durable tumor control. These findings provide strong mechanistic and translational rationale for clinical evaluation of this strategy in NF1-driven peripheral nerve tumors."

Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • NF1

An appendiceal cancer organoid biobank identifies phenotypic evolution and druggable dependencies of peritoneal carcinomatosis. (PubMed, Dev Cell) - "Single-cell profiling reveals dedifferentiation from differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. We identify KRASMULTI-ON inhibitor RMC-7977 and the Wnt-targeting tyrosine kinase inhibitor WNTinib as clinically actionable strategies to target AC-PC more effectively."

Journal • Appendix Cancer • Gastrointestinal Cancer • Oncology • Peritoneal Cancer • Solid Tumor • KRAS

Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma. (PubMed, Cancer Res) - "Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). 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

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer. (PubMed, bioRxiv) - "KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy."

Journal • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KEAP1 • KRAS

Reprogramming of the non-pathogenic E. coli surface architecture to create next-generation immune engagers for potent cancer therapies (AACR 2026) - "In syngeneic A20 and KPC tumor models, mice received intravenous LIME ± anti-PD-1 (i.p.) or RMC-7977 (oral). In DLL3⁺ H69 xenografts, NSG mice were infused with human CD3⁺ T cells followed by LIME, benchmarked against the FDA-approved engager Tarlatamab... LIME represents a versatile platform that enables localized, immune engagement, overcomes major barriers in solid tumors, and outperforms existing immune engagers while maintaining a favorable safety profile."

Brain Cancer • Glioblastoma • Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Small Cell Lung Cancer • Solid Tumor • ANXA5 • CD69 • DLL3 • IL2RA • MSLN • NKG2D

Harnessing lipid metabolism to treat drug-tolerant persister cells (AACR 2026) - "To test this, we induced DTPs in murine PDAC cell lines using the KRAS-targeted therapy RMC-7977 and treated them with PUFAs, including alpha-eleostearic acid (ESA)...We are now evaluating whether this approach can limit relapse by targeting minimal residual disease in animal models of PDAC treated with KRAS inhibitors. These findings reveal a diet-based strategy that exploits metabolic vulnerabilities of therapy-persistent PDAC cells and may reduce the risk of disease recurrence."

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

Hypoxia enhances sensitivity to RAS inhibition in PDAC (AACR 2026) - "The RAS(ON) multi-selective inhibitor daraxonrasib has demonstrated clinical activity in PDAC and is currently being evaluated in Phase 3 trials; however, monotherapy resistance still emerges underscoring the need to identify biological processes that enable tumor cell survival following RAS inhibition. Pharmacologic inhibition of mitochondrial respiration under normoxia also enhanced RMC-7977 sensitivity. Together, these findings reveal that RMC-7977 reduces glucose uptake and shifts cells toward oxidative metabolism and uncovers a potential metabolic vulnerability involving the PDAC tumor microenvironment that has the potential to enhance the impact of RAS inhibition."

Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

Dual targeting of PARP and RAS enhances antitumor activity in pancreatic cancer (AACR 2026) - "We tested the effect of PARPi (olaparib) in combination with two RAS inhibitors: A tool RAS(ON) -multi-selective inhibitor RMC-7977 and a tool RAS(ON) G12D-selective inhibitor RMC-9945 (RM-044) in-vitro and in-vivo, utilizing specific models' systems based on BRCA and KRAS status (n=12).In vitro, PDCs were treated with olaparib, RMC-7977, RMC-9945 and combinations for 5 days. Notably, most models were generated from tumors obtained from patients at clinical resistance to standard of care treatment reflecting models with aggressive biology. Thus, these findings support further evaluation of combinational treatment of both RAS(ON) and PARP inhibition in this population."

Oncology • Pancreatic Cancer • Solid Tumor • BRCA • BRCA2 • KRAS • PARP1

RAS(ON) multi-selective inhibitors stimulate the hydrolysis of RAS-GTP to RAS-GDP and drive synergistic combination benefit with KRAS(OFF) inhibitors in G12 mutant tumors (AACR 2026) - "In addition to suppressing RAS signaling by disrupting interactions with downstream effectors via steric occlusion, the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) and the preclinical tool compound RMC-7977 also activate RAS(ON) GTPase activity and promote the conversion of RAS(ON) to RAS(OFF). In vivo, the combination of daraxonrasib and KRAS(OFF) inhibitors at well-tolerated doses drove deep and durable RAS pathway suppression and tumor regressions in various KRAS G12 mutant xenograft models, including models with reduced sensitivity to either single agent, e.g., those with mutant KRAS amplification. Overall, these preclinical findings provide a mechanistic rationale for, and experimental evidence in support of, the clinical evaluation of the combination of a RAS(ON) multi-selective inhibitor that stimulates the GTPase activity of oncogenic KRAS mutants with a KRAS(OFF) inhibitor as a potential therapeutic strategy to maximize RAS inhibition and enhance..."

Oncology • KRAS

Synergistic antitumor activity of tumor-treating fields and multiselect-RAS (ON) inhibitor RMC-6236 in pancreatic ductal adenocarcinoma (AACR 2026) - "This compound shares structural similarities with RMC-7977 and exhibits a conserved binding site and interaction pattern within the tri-complex formed between active RAS (RAS(ON)) proteins and cyclophilin A (CypA)...The PANOVA-3 trial demonstrated that TTFields combined with gemcitabine plus nab-paclitaxel improved survival, pain control, and quality of life in locally advanced PDAC...Additionally, western blot analysis was performed to assess changes in KRAS protein expression, a key PDAC biomarker. Overall, our results demonstrate that the combination of TTFields and RMC-6236 significantly inhibits PDAC cell growth, migration, and survival at sub-IC₅₀ concentrations, suggesting a promising alternative therapeutic approach for PDAC management."

Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

KRAS amplification creates a targetable pMHC antigen for T cell engager therapy to overcome KRAS inhibitor resistance (AACR 2026) - "KRAS pathway inhibition further increased antigen levels: treatment of 10 nM RMC-7977 in COR-L23 cells (G12V; KRAS CN=16), produced a 2.5× rise in surface HLA and an 8-fold increase in kAMP.A2, reaching ~4,000 CPC at 48 h. KRAS amplification thereby establishes an exploitable pMHC therapeutic window—analogous to gp100 or PRAME—that is further broadened by KRAS inhibition...Our data demonstrate that KRAS amplification—whether intrinsic or emerging under therapeutic pressure—creates a robust, tumor-amplified pMHC antigen with exceptional potential for therapeutic exploitation. PK313 enables selective targeting of KRAS-amplified tumors as a monotherapy or in combination with KRAS small molecule inhibitors to enhance treatment durability and provides a therapeutic strategy for A*02:01 patients (~42% in US population), who are currently excluded from A*03/A*11 KRAS-mutant neoantigen TCR-T/CAR-T/TCE programs."

IO biomarker • Gastroesophageal Cancer • Oncology • Solid Tumor • HLA-A • HRAS • KRAS • NRAS • PRAME

Comprehensive genomic profiling of angiosarcoma cells reveals widespread activation of the RAS pathway (AACR 2026) - "Our ongoing work involves evaluating the in vivo efficacy of RMC-7977 in angiosarcoma xenograft models harboring both mutant and wild-type RAS. Furthermore, we will dissect the molecular mechanism underlying this broad RAS dependency by assessing the impact of RMC-7977 on activated RAS and downstream signaling, further supporting the rationale for its clinical use in angiosarcoma."

Angiosarcoma • Oncology • Sarcoma • Solid Tumor • CDK4 • CDKN2A • KDR • NRAS • PIK3CA • TP53

Pre-treatment with azacytidine sensitizes RAS mutated secondary AML to the pan-RAS inhibitor RMC-7977 (AACR 2026) - "Most patients with sAML are treated with combinations of hypomethylating agents, such as azacytidine, together with venetoclax, a BCL-2 inhibitor. Ongoing studies aim to elucidate the underlying molecular mechanisms, including the potential role of methylation changes in modulating oncogenic signaling dependencies. Together, these findings provide a strong rationale for continued evaluation of RAS inhibitors as part of combination treatment strategies for RAS-mutated AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • KRAS • NRAS • PTPN11

DIRAS3 mimetic peptide achieves dual MAPK and PI3K pathway suppression across KRAS hotspot mutations (AACR 2026) - "Reduced PI3K activity correlated with enhanced sensitivity to the DIRAS3 peptide, and cells harboring Q61X mutations, which are less responsive to RMC-7977, remained equally responsive to the DIRAS3 peptide. Collectively, these results indicate that DIRAS3 provides a dual-pathway blockade of MAPK and PI3K signaling across diverse KRAS mutations, including Q61X variants that are refractory to existing agents, supporting its development as a broad-spectrum therapeutic for RAS-driven cancers."

Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • DIRAS3 • EGF • KRAS

RAS(ON) multi-selective inhibition remodels cancer-associated fibroblast subtypes and extracellular matrix in pancreatic cancer (AACR 2026) - "In summary, we report that RMC-7977 switches the myCAF-dominant CAF landscape towards an iCAF-enriched TME through the KRAS-SHH axis and this alters TME composition and reduces tumor stiffness through ECM remodeling. Future studies will examine the impact of these finding on drug delivery, tumor invasiveness, tumor differentiation state."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • HRAS • IL6 • KRAS • NRAS • PDX1 • SHH

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. 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

Active RAS inhibition intercepts pancreas cancer in mice (AACR 2026) - "Notably, long-term cancer interception with RMC-7977 conferred a survival benefit of 25 weeks (p<0.0001) compared to the use of RMC-7977 at the time of cancer diagnosis in KPC mice. We conclude that targeted pharmacological cancer interception reduces premalignant PanIN lesions and substantially extends survival in preclinical models of PDAC, supporting clinical evaluation of RAS inhibitors for pancreatic cancer interception."

Late-breaking abstract • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PDX1

BMAL2 is a KRAS-driven master regulator of hypoxic adaptation and EMT in pancreatic ductal adenocarcinoma (AACR 2026) - "Pharmacologic inhibition of RAS using the pan-RAS(ON) inhibitor RMC-7977 significantly reduced BMAL2 activity both in vitro and in vivo without altering BMAL2 expression levels, indicating a post-translational regulatory mechanism...By coordinating transcriptional and metabolic programs required for survival under extreme hypoxic conditions, BMAL2 enables PDAC cells to adapt to and thrive within their uniquely hostile tumor microenvironment. These results provide mechanistic insight into how KRAS signaling drives pancreatic cancer biology and highlight BMAL2 as a key regulator of tumor fitness within the hypoxic tumor ecosystem."

Oncology • Pancreatic Ductal Adenocarcinoma • ARNTL • BMAL1 • EPAS1 • HIF1A • KRAS • VIM

Combining RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors overcomes sotorasib resistance driven byKRASG12C amplification or NRASG13R mutation (AACR 2025) - "Amplification of the KRASG12C mutant allele and acquisition of NRAS mutations have been reported as resistance mechanisms in tumors progressing on sotorasib and adagrasib...We generated five sotorasib-resistant cell lines from relapsed tumors of sotorasib-treated H358 xenografts (MR1-MR5) and two vehicle-treated tumors (MV1 and MV2). We created an additional isogenic cell line model, H358-MX1, by treating H358 cells with sotorasib and a SHP2 inhibitor, RMC-4550...In H358-MX1 mouse xenografts, RMC-7977 + RMC-4998 significantly inhibited tumor growth compared to single-agent treatments or other combination regimens. These preclinical data suggest that combination of RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors overcome resistance to KRASG12C (OFF) inhibitors driven by KRASG12C amplification and secondary NRASG13R mutation in KRASG12C mutated lung cancer models."

Lung Cancer • Oncology • Solid Tumor • KRAS • MX1 • NRAS

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

RAS-GTP inhibition modulates Hedgehog signaling, suppressing myCAFs and promoting iCAFs in pancreatic ductal adenocarcinoma (AACR 2024) - P1/2 | "RMC-7977 is a potent inhibitor of GTP-bound RAS proteins (RAS(ON), including both wild type and mutant variants of KRAS, NRAS, and HRAS. The related investigational agent, RMC-6236, is a first-in-class, potent, orally bioavailable, RASMULTI(ON) inhibitor currently in Phase 1/1b clinical trials (NCT05379985)...Consistent with prior studies of Smoothened inhibitors, the depletion of myCAFs from RAS-GTP inhibition was associated with the rapid opening and hypersprouting of intra-tumoral blood vessels. Ongoing studies using the mutant-selective KRASG12D inhibitor RM-044 should discriminate between direct effects of wild type RAS inhibition in CAFs versus the paracrine consequences of mutant RAS inhibition in malignant epithelial cells."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • HRAS • KRAS • NRAS • SHH

Resistance to RAS-GTP inhibition in models of pancreatic ductal adenocarcinoma arises downstream of RAS effectors (AACR 2024) - P1/2 | "RMC-7977 is a potent inhibitor of GTP-bound RAS proteins (RAS(ON)), including both wild type and mutant variants of KRAS, NRAS, and HRAS. The related investigational agent, RMC-6236, is a first-in-class, potent, orally bioavailable, RASMULTI(ON) inhibitor currently in Phase 1/1b clinical trials (NCT05379985)...The observed range of potential resistance mechanisms suggests that RAS-GTP inhibition imposes a narrow evolutionary path to the development of acquired resistance in this context. These preclinical findings may help inform the ongoing development of investigational RAS inhibitors and the design of potential combinatorial treatment strategies to forestall resistance."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • HRAS • KRAS • NRAS