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.

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.

RRASQ87L and RRAS2Q72L are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of RRAS/RRAS2 into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRASQ87L/RRAS2Q72L-mutant lung cancers.

RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

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.

P1, N=128, Terminated, Chugai Pharmaceutical | N=195 --> 128 | Trial completion date: Aug 2026 --> Nov 2025 | Active, not recruiting --> Terminated | Trial primary completion date: May 2026 --> Nov 2025; Sponsor decided to discontinue this study upon having LPLV.

P2, N=30, Recruiting, Neonc Technologies, Inc. | Trial completion date: Sep 2026 --> Jun 2027 | Trial primary completion date: Sep 2025 --> Dec 2026

P1/2, N=49, Recruiting, Neonc Technologies, Inc. | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Oct 2025 --> Mar 2026

P3, N=501, Active, not recruiting, Revolution Medicines, Inc. | Recruiting --> Active, not recruiting

P1, N=12, Not yet recruiting, Neonc Technologies, Inc. | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2025 --> Oct 2026

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

P1, N=91, Not yet recruiting, Adlai Nortye Biopharma Co., Ltd.