KRAS G12C

Methylation signature may be combined with genomic analysis to personalize therapeutic strategies for KRAS p. G12C mutated NSCLC patients. "Multiomic" analysis of tumor-informative molecular targets (genomic profile, methylation status) lay the basis for dynamic fingerprints of NSCLC patients preventing early relapses and augmenting clinical benefits of targeted therapies.

Pharmacologic inhibition of KRAS G12C reverse the mechano-phenotype, while introducing KRAS G12C into healthy cells recapitulated it. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell's mechanical state could be a powerful complement to emerging KRAS-directed therapies.

BBO-8520 exerted more potent and sustained inhibition of KRAS G12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRAS G12C (OFF)-only inhibitor...Moreover, in some contexts, disruption of RAS-PI3Kα further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3Kα-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3Kα-AKT to improve the response to KRAS inhibitors.

Furthermore, combining sotorasib with either a DHX9 inhibitor or an SOS1 inhibitor significantly enhances its anti-tumor efficacy in both KRASG12C-mutant and sotorasib-resistant models. These findings provide previously uncharacterized mechanistic insights to guide therapeutic strategies aimed at overcoming sotorasib resistance.

RICTOR mutations were associated with a high-risk subset of EGFR-mutant metastatic lung adenocarcinoma characterized by more aggressive clinical features and worse survival. These findings suggest the need for prospective validation and support the potential integration of RICTOR status into molecular risk stratification frameworks for precision oncology.

This study assessed clinical features and survival outcomes according to KRAS mutation in a real-life population of nsq-NSCLC patients treated with first-line platinum-pemetrexed-pembrolizumab.MethodsThis is a retrospective-prospective study including patients with nsq-NSCLC who received first-line platinum-pemetrexed-pembrolizumab from 4 September 2018 in 33 Italian Centers.ResultsAmong the 765 patients included in this analysis, 121 (15.8%) had KRAS p.G12C mutation, 201 (26.3%) KRAS non-p.G12C mutation and 443 (57.9%) KRAS WT. No difference in OS was found between KRAS p.G12C and KRAS non-p.G12C (15.9 vs 17.0 months, HR 0.93, 95% CI: 0.66-1.31, p=0.676).Median progression-free survival was significantly shorter in KRAS-mutated compared to KRAS WT patients (8.8 vs 10.8 months; adjusted HR 1.29, 95% CI 1.04-1.59, p=0.018), with no differences between KRAS p.G12C and KRAS non-p.G12C (8.8 vs 8.8 months, HR 0.95, 95% CI: 0.70-1.30, p=0.756).ConclusionsKRAS mutation showed a potential negative predictive role in advanced nsq-NSCLC treated with first-line chemo-immunotherapy. The impact of co-mutations and post-progression outcomes warrants further investigation.

Treatment with 5-FU plus panitumumab and sotorasib could be a promising alternative to 5-FU ± targeted therapy in first-line setting in frail/elderly patients with unresectable KRAS G12C-mutated CRC.

Cytology supernatants preserved in CytoLyt® are a feasible substrate for rapid, cartridge-based molecular testing using the Idylla™ platform. This approach can serve as a complementary or rescue strategy when cellular slide preparations or FFPE tissue is limited or NGS fails, enabling faster access to actionable molecular results in NSCLC.

P1, N=15, Recruiting, Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) | Not yet recruiting --> Recruiting | Phase classification: P2 --> P1

P2, N=28, Not yet recruiting, Shanghai Juncell Therapeutics

P1, N=830, Recruiting, Merck Sharp & Dohme LLC | N=167 --> 830