KRAS Q61

These data support RRAS Q87L and RRAS2 Q72L as bona fide lung cancer drivers and nominate RRAS/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Aug 2025 --> Jul 2026

KRAS variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.

Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations...RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.

P2, N=38, Not yet recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

These findings provide evidence for a neomorph SHOC2-(canonical)RAS protein interaction that is pharmacologically actionable and relevant to cancer sustenance. Overall, this work provides the concept validation and foundation for developing new therapies at the core of the RAS signalling pathway.

The clinicopathological characteristics were analyzed, and the possible mechanisms were further discussed. However, due to the CRC patients with co-mutations in two exons of the KRAS are exceedingly rare, a cohort study with more patients' clinical data is urged.

These findings show how G12D mutation redefines KRAS's dynamic network, leading to persistent activation through enhanced residue coupling rather than mere local disruption. Our results suggest novel therapeutic strategies focused on modulating protein dynamics rather than targeting specific binding sites, potentially offering new approaches to combat KRAS-driven cancers.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2025 --> Jan 2026

KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.

Subsequent bioinformatics analysis showed that the mutation was highly deleterious and affected protein function to a greater extent. This identification may further improve the prognosis of CRC and benefit subsequent treatment choices.

KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.