Targeting the RAS Pathway: Pan-KRAS Inhibitors, Resistance Mechanisms, and Next-Generation Strategies

RAS mutations, most commonly in KRAS, drive a substantial share of human cancers, including pancreatic, colorectal, and non-small cell lung cancer. For decades RAS was considered undruggable, but the recent success of mutant-specific inhibitors targeting KRAS G12C has transformed the field and validated RAS as a tractable therapeutic target. These agents, however, address only a fraction of oncogenic RAS variants, and acquired resistance—through secondary RAS mutations, bypass signaling, or clonal selection—limits durable clinical benefit. This has driven interest in pan-RAS and pan-KRAS inhibitors capable of engaging multiple mutant and wild-type isoforms, along with combination strategies designed to preempt or overcome resistance. The U.S. Food and Drug Administration recently approved a new drug targeting KRAS named RASONQUE (daraxonrasib) for the treatment of adults with metastatic pancreatic adenocarcinoma who received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. This is considered the new standard of care for patients with previously treated metastatic pancreatic cancer after clinical trial results in this population showed a doubling of survival compared to chemotherapy.This Research Topic focuses on the current state and future direction of RAS-pathway–targeted therapy, with emphasis on pan-KRAS inhibition, the mechanisms underlying resistance to both mutant-specific and pan-RAS agents, and strategies to extend durability of response. We welcome contributions addressing the biochemistry and structural pharmacology of pan-RAS and pan-KRAS inhibitors, including covalent and non-covalent approaches and their selectivity profiles across RAS isoforms and mutational contexts. Work characterizing mechanisms of intrinsic and acquired resistance—including downstream pathway reactivation, RAS-independent bypass signaling, epithelial-to-mesenchymal transition, and tumor microenvironment–mediated adaptation—is encouraged, as is research on rational combination approaches pairing RAS inhibitors with downstream pathway inhibitors, immunotherapies, or agents targeting parallel signaling nodes such as Wnt/β-catenin.Preclinical modeling is central to this field, and we invite studies using genetically engineered mouse models, patient-derived xenografts, organoids, and 3D tumor systems to evaluate efficacy, resistance evolution, and pharmacodynamics of next-generation RAS-targeted agents. Studies linking RAS inhibition to immunomodulatory effects—including tumor immunogenicity, T-cell priming, and the interplay between RAS signaling and the tumor immune microenvironment—are particularly relevant given growing interest in combining RAS-targeted and immune-based therapies. Biomarker-driven approaches to patient selection, including genomic and transcriptomic signatures predictive of response or resistance, are also within the scope of this Research Topic.This Research Topic is not limited to any single tumor type, though pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer are expected to be well represented given their high prevalence of RAS pathway alterations. We particularly encourage submissions that advance mechanistic understanding of pan-RAS/pan-KRAS inhibitor pharmacology, define resistance liabilities before they emerge in the clinic, or propose next-generation combination strategies grounded in a clear rationale. Contributions spanning medicinal chemistry, structural biology, cancer cell biology, pharmacology, and translational oncology are all welcome, provided they advance the field’s understanding of how to durably target RAS-driven malignancies.Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: Donald Buchsbaum, Gary Piazza, Adam Keeton Source: https://www.frontiersin.org/research-topics/86104/targeting-the-ras-pathway-pan-kras-inhibitors-resistance-mechanisms-and-next-generation-strategies