RAS wild-type

The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.

This study demonstrated that dynamic changes in plasma RAS mutation status may occur during disease progression in patients with mCRC, potentially reflecting tumor clonal evolution. The observed survival advantage in patients with RAS mutation clearance suggests potential prognostic relevance. Reassessment of RAS status using liquid biopsy at disease progression may provide clinically relevant information; however, these findings should be considered exploratory and require prospective validation in larger cohorts.

This study is the first to examine p27 localization in WT KRAS CRC. The observed association between WT KRAS expression and cytoplasmic p27 localization highlights a potential mechanism contributing to tumour progression through altered p27 function.

Moreover, we observed that KRASG12C/EML4-ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4-ALK bypasses KRASG12C inhibition by activating wild-type RAS, highlighting an additional therapeutic opportunity for multi-selective RAS inhibitors under clinical investigation.

Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.

P1/2, N=58, Completed, Associacio Per A La Recerca Oncologica | Phase classification: P=N/A --> P1/2 | --> Completed

MiR-31-3p is a promising predictive biomarker for cetuximab response in RAS wild-type mCRC, with low expression consistently associated with improved outcomes. However, tumor sidedness may modulate its predictive value. Prospective validation studies with standardized assays are needed before clinical implementation. Integration of miR-31-3p with existing markers could help identify patients unlikely to benefit from anti-EGFR therapy.

For OS, both cetuximab + chemotherapy [hazard ratio (HR)=0.853; 95% CI: 0.775-0.938; P=0.001] and panitumumab + chemotherapy (HR=0.855; 95% CI: 0.738-0.992; P=0.038) exhibited statistically significant superiority compared with bevacizumab + chemotherapy...In the present sensitivity analysis, UDP glucuronosyltransferase family 1 member A1-guided bevacizumab + 5-fluorouracil, leucovorin and irinotecan demonstrated favorable outcomes, with OS and PFS P-scores of 0.932 and 0.992, respectively; however, these findings were derived from a single trial with limited comparability...Treatment benefit from anti-EGFR therapy was markedly influenced by primary tumor location, with notable benefit observed in left-sided tumors and no benefit in right-sided tumors. These findings support tumor sidedness-guided treatment selection in clinical practice, favoring anti-EGFR-based therapy for left-sided and bevacizumab-based therapy for right-sided RAS wild-type mCRC.

Mouse embryonic fibroblasts transformed with KRASG12C also contain more saturated lipids than KRASG12D MEFs. Thus, activities of KRAS mutants depends on lipid acyl chain remodeling in an allele-specific manner.

The NTZ-AG regimen demonstrated meaningful anti-tumor activity and an acceptable safety profile as first-line therapy for unselected advanced pancreatic cancer patients, providing a rational basis for larger randomized controlled trials. This trial was registered at the Chinese Clinical Trial Register (ChiCTR) under the registration number ChiCTR2300072843 having URL https://www.chictr.org.cn/showprojEN.html?proj=198791.

Although recent advances have led to covalent inhibitors such as Sotorasib and Adagrasib for the KRAS G12C mutation, effective therapies for other common variants, particularly KRAS G12D, which is highly prevalent in aggressive pancreatic cancers, remain limited...To further validate the predictive capability of the models, two compounds identified as high-confidence candidates, Cobimetinib and Etrasimod, were selected for experimental evaluation...While additional biochemical and pathway-level studies are required to confirm direct target engagement, these results support the model's utility in prioritizing candidate compounds with allele-specific activity profiles. Overall, this study provides a data-driven framework for identifying potential KRAS-targeted therapies and highlights the value of integrating machine learning predictions with experimental validation.

P1, N=18, Recruiting, Joint Biosciences Ltd.