RMC-7977

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.

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.

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.

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.

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.

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.

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.

We found that KRAS-mutant CRC cell lines were sensitive to the RAS(ON) multiselective RAS inhibitor RMC-7977, given that treatment resulted in RAS-RAF-MEK-ERK pathway inhibition; halted proliferation; and, in some cases, induced apoptosis...Our findings demonstrate the power of reporter-assisted screening together with single-cell analyses for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract the emergence of resistant cancer cells.

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.

In conclusion, this study employed high-throughput CRISPR/Cas9 sgRNA screening to identify the enhanced anti-cancer effects when combining EGFR inhibitors with pan-RAS inhibitors in multiple human KRAS-mutated cancer cell lines as well as a mouse syngeneic tumor model. This synergy underscores the potential for a combinational therapy strategy, leveraging EGFR and pan-RAS inhibitors to improve treatment outcomes for patients with KRAS-driven cancers.

RAS(ON) multi-selective inhibitors, such as daraxonrasib (RMC-6236) and RMC-7977, target the active state of RAS, with potent anti-tumor activity in PDAC murine models. Moreover, the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone. In summary, concurrent inhibition of mutant and wild-type RAS is active in concert with T cell immunotherapy, revealing RAS(ON) multi-selective inhibitors as a potential therapeutic immuno-sensitizing strategy in PDAC.