ArticleMolecular cancer therapeutics2025
Pan-KRAS Inhibitors BI-2493 and BI-2865 Display Potent Antitumor Activity in Tumors with KRAS Wild-type Allele Amplification.
Article in Molecular cancer therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Daraxonrasib and the era of pan-RAS inhibition: mechanisms, clinical advances, and resistance landscapes.Experimental hematology & oncology · 2026Review
- KRAS is required for plexiform neurofibroma formation and represents a targetable vulnerability in established tumors.Science advances · 2026Article
- Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel, CNS-Penetrant KRAS G12C Inhibitor.Journal of medicinal chemistry · 2026Article
- Structure-Informed Design of Distinct Parallel G-Quadruplex Stabilizers for KRAS-Driven Cancer Therapy.Angewandte Chemie (International ed. in English) · 2026Article
- Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.Leukemia · 2026Article
- Multi-modal data integration reveals functionally credible predictive biomarkers in ovarian cancer.Genome medicine · 2026Article
- KRAS inhibition is an effective therapy for appendiceal adenocarcinoma.Journal of hematology & oncology · 2026Article
- Review
- Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer.Nature communications · 2026Article
- Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF.bioRxiv : the preprint server for biology · 2026Article
- KRAS inhibition is an effective therapy for appendiceal adenocarcinoma.bioRxiv : the preprint server for biology · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- UnlockingCurrent oncology (Toronto, Ont.) · 2026Review
- Ovarian Cancer Susceptibility and Chemosensitivity to KRAS Modulation.International journal of molecular sciences · 2026Article
- RAS Mutation-Specific Responses to Paralog- and State-Selective RAS Inhibitors.Molecular cancer research : MCR · 2026Article
- Genomic innovations in cancer prevention, diagnosis, prognosis and precision therapeutics.Frontiers in genetics · 2026Review
- Therapeutic inhibition of RAS in non-small cell lung cancer.Frontiers in oncology · 2026Review
- Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches.Current oncology (Toronto, Ont.) · 2025Review
- An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.Science translational medicine · 2025Article
- KRAS: the Achilles' heel of pancreas cancer biology.The Journal of clinical investigation · 2025Review
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Authors and funding
18 authors.
Funding
Abstract
KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS-mutant alleles in patients with cancer. We report that KRAS wild-type (WT)-amplified tumor models are sensitive to treatment with the small-molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent antitumor activity in preclinical models of cancers driven by KRAS-mutant proteins. In this study, we used the high-throughput cellular viability Profiling Relative Inhibition Simultaneously in Mixtures assay to assess the antiproliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS WT-amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS "OFF" inhibitor is better suited to treat KRAS WT-amplified tumors than a KRAS "ON" inhibitor. KRAS WT amplification is common in patients with gastroesophageal cancers in which it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent antitumor activity in vitro and in vivo in KRAS WT-amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacologic inhibition of KRAS shows antitumor activity in preclinical models of cancer with KRAS WT amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.
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