P=N/A, N=0, Available, Revolution Medicines, Inc.

Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases...We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.

Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

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.

P1, N=392, Recruiting, TheRas, Inc., d/b/a BBOT (BridgeBio Oncology Therapeutics) | N=91 --> 392

P2/3, N=74, Not yet recruiting, Revolution Medicines Inc.

P1/2, N=105, Not yet recruiting, Institut De Recherches Internationales Servier IRIS

Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA...Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

KRAS mutations represent the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), defining a clinically heterogeneous subset that was historically considered "undruggable." The identification of a mutant-specific allosteric pocket in KRAS G12C led to the development of sotorasib and adagrasib, fundamentally altering the treatment paradigm for pretreated patients...This review provides a comprehensive synthesis of the expanding therapeutic landscape, moving beyond G12C-selective inhibition toward next-generation allele-specific agents, such as G12D inhibitors, and groundbreaking pan-RAS/RAS(ON) tri-complex inhibitors like RMC-6236...As the field transitions from single-allele blockade to multi-selective RAS(ON) inhibition and rational vertical pathway targeting, personalized, biomarker-guided treatment algorithms will be essential. By outlining the trajectory from G12C to pan-RAS strategies, this review captures the evolving precision oncology framework necessary to achieve durable clinical benefit in KRAS-mutant NSCLC.

We evaluated KRAS G12D -specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRAS mut organoid and orthotopic PDX models of AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

We report the case of a patient with metastatic foot melanoma enrolled in a clinical trial of the anti-RAS agent RMC-6236 who developed chronic bilateral corneal epithelial defects and thinning, likely secondary to the systemic effects of targeted therapy. This case highlights the ocular surface toxicity associated with systemic anticancer therapies affecting rapidly dividing cells and the overall importance of multidisciplinary medical management of these systemic therapeutics.

While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling...Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models. In conclusion, our findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.