RAS and KRAS Inhibitors in Cancer Therapeutic Mechanisms and Resistance: Scoping Review with ☸️SAIMSARA

Name: SAIMSARA Evidence Object visceral::RAS_AND_KRAS_CANCER_PM
Creator: SAIMSARA
License: https://saimsara.com/license/

SAIMSARA

doi:10.62487/saimsaradc4d1e0f

SAIMSARA Journal

Machine-Readable Science • ISSN 3054-3991

RAS and KRAS Inhibitors in Cancer Therapeutic Mechanisms and Resistance: Scoping Review with ☸️SAIMSARA

Gastrointestinal & Metabolic Health

Issue 9, Volume 1, 2026

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DOI: 10.62487/saimsaradc4d1e0f

Editorial note

• Last update: 2026-06-01 19:19:41

What is this paper about

RAS/KRAS inhibition has finally moved from “undruggable” promise to therapeutic reality, but this review shows why single-agent targeting is rarely enough. The full read maps 705 original studies to clarify how allele-specific, pan-RAS, RAS(ON), combination, resistance-monitoring, and immune/radiotherapy strategies may shape the next generation of durable cancer control.

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Abstract: To map and synthesize original research on RAS and KRAS inhibitors in cancer, with emphasis on direct inhibitors, pan-RAS or pan-KRAS approaches, allele-specific strategies, resistance mechanisms, and rational combinations that may improve treatment selection and durability of response. The review uses 308 references and builds its evidence map from 703 original studies with 74272 total participants/sample observations (topic-deduplicated ΣN). This scoping review indicates that RAS/KRAS inhibition in cancer is therapeutically actionable but is best understood as a systems-level intervention requiring anticipation of pathway reactivation. Across allele-specific, pan-KRAS, pan-RAS, and RAS(ON) approaches, durable control was repeatedly limited by adaptive RAS–MAPK reactivation, receptor tyrosine kinase feedback, and wild-type RAS compensation, with acquired RAS/MAPK alterations emerging in 46% of inhibitor-treated patients and more frequently in colorectal than non-small cell lung cancer (69% versus 26%). The recurrent signal supports a shift toward broader RAS-state targeting and rationally designed combinations with EGFR, SHP2, or MEK partners rather than direct inhibition alone. Practically, this highlights the value of serial molecular profiling to detect heterogeneous, often polyclonal escape mechanisms. Future prospective, longitudinal studies defining allele- and histology-specific resistance trajectories are needed to translate these largely preclinical signals into durable clinical benefit.

Keywords: RAS inhibitors; KRAS inhibitors; KRAS-mutant cancer; Pan-KRAS inhibition; RAS(ON) inhibitors; Sotorasib resistance; MAPK signaling; Combination therapy; Colorectal cancer; Non-small cell lung cancer

Review Stats

Final search date and database lock: 2026-06-01 20:06:23 CEST
Plan: Pro (expanded craft tokens; source: PubMed)
Source: PubMed
Total Abstracts/Papers: 1146
Downloaded Abstracts/Papers: 1146
Included original and non-original Abstracts/Papers (all): 1077
Included original Abstracts/Papers (Vote counting by direction of effect): 703
Reference Index (links used in paper): 308
Total participants/sample observations (topic deduplicated ΣN): 74272

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Reference Index (306)

[1] KRAS inhibitors: resistance drivers and combinatorial strategies. — https://doi.org/10.1016/j.trecan.2024.11.009
[2] Targeting KRAS in cancer. — https://doi.org/10.1038/s41591-024-02903-0
[3] Response and Resistance to RAS Inhibition in Cancer. — https://doi.org/10.1158/2159-8290.cd-25-0349
[4] Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. — https://doi.org/10.1038/s41586-024-07205-6
[5] The next-generation KRAS inhibitors…What comes after sotorasib and adagrasib? — https://doi.org/10.1016/j.lungcan.2024.107886
[6] Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. — https://doi.org/10.1038/s41586-023-06123-3
[7] Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236. — https://doi.org/10.1016/j.drudis.2024.104250
[8] Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges. — https://doi.org/10.1038/s41392-025-02473-8

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