P1/2, N=120, Not yet recruiting, Betta Pharmaceuticals Co., Ltd.

As such, the BCL-2 inhibitor venetoclax further enhanced RMC-6236-mediated killing by disrupting RMC-6236 enhanced BIM:BCL-2 complexes. RMC-6236 is a clinically relevant drug that can successfully target the MAPK pathway in these cancers. This study supports expanded clinical testing of this novel therapy to this important subset of neuroblastoma.

These findings are consistent with a phase I trial of bi-steric mTORC1 inhibitor RMC-5552, showing anti-tumor activity in patients with EC. PDXs with KRAS co-mutations regrew after RMC-6272 treatment, which was prevented by the addition of the RAS(ON) multi-selective inhibitor RMC-7977...Single mutant tumors are sensitive to PI3K inhibition but those with both mutations are insensitive to PI3K or AKT inhibition but are exquisitely dependent on mTORC1 kinase. This provides strong preclinical rationale for targeting mTORC1, alone or combined with RAS inhibition (in RAS co-mutant tumors), as an effective therapeutic strategy.

Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable immune suppressive profile to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate for the treatment of KRAS-mutant PDAC capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

P1, N=32, Not yet recruiting, Vividion Therapeutics Inc.

P1/2, N=130, Recruiting, Revolution Medicines Inc.

P1, N=91, Recruiting, Adlai Nortye Biopharma Co., Ltd. | Not yet recruiting --> Recruiting

Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.

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.