KRAS G12C

We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.

This pooled analysis confirmed the robust efficacy and manageable safety of garsorasib in KRAS G12C-mutated NSCLC.

Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRASG12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group.

Despite the historical challenges in targeting KRAS-mutant proteins, the findings of this study support the potential of natural products as scaffolds for anticancer drug discovery as a source for developing novel anticancer therapies. The identified phytochemicals from C. officinalis such as calendasaponin D and procyanidin A2 may serve as potential leads for future preclinical and experimental validation against KRAS-driven malignancies.

Olomorasib + pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with KRAS G12C-mutant advanced NSCLC across PD-L1 expression levels, especially in the high PD-L1 first-line setting.

In this review, we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS. We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies, describe their mechanisms of action, and offer insights into the current clinical trial status of each of these approaches.

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

This review discusses current knowledge on proteomic alterations associated with oncogenic KRAS mutations, with particular focus on allele-specific proteome signatures and the roles of post-translational modifications (PTMs) of KRAS in modulating the functional networks. Furthermore, we highlight recent therapeutic advances targeting KRAS variants and discuss emerging resistance mechanisms from a proteomics-informed perspective.

Recent phase I/II trials of KRAS G12C inhibitors have shown promising results, and the phase III CodeBreaK 300 study confirmed that sotorasib combined with panitumumab significantly improved efficacy compared with standard treatment, establishing a new therapeutic option for KRAS G12C-mutant metastatic CRC. Strategies under investigation include targeting alternative signaling pathways, developing next-generation inhibitors and specific degraders, and exploring multi-mechanism or multi-target combination strategies. This review systematically outlines the development of KRAS G12C inhibitors in mCRC, summarizes resistance mechanisms, and discusses emerging combination regimens, aiming to provide a theoretical basis and future directions for treatment optimization.

P1, N=9, Active, not recruiting, Chinese PLA General Hospital | Recruiting --> Active, not recruiting | N=15 --> 9 | Trial primary completion date: Dec 2025 --> Jun 2026

Based on mechanistic investigations, we propose that KRAS mutations impair intrinsic hydrolysis by disrupting the interactions needed to align the nucleophilic water molecule with GTP for nucleophilic attack. These results can assist small-molecule inhibitor design and also benefit the development of other therapeutic strategies, such as rescuing hydrolysis.

The mutation-based signature established herein represents a robust biomarker for identifying patients with advanced NSCLCs who are most likely to benefit from ICB therapy, including those with targetable oncogene alterations.