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Ref Type Journal Article
PMID (41661652)
Authors Patel HV, Smith AE, Chan S, Gasendo JG, Jombik A, Greer JE, Samantaray T, Kessler L, Mitra A, Zhu X, Liu YA, Burrows F, Malik S
Title The Farnesyl Transferase Inhibitor Darlifarnib (KO-2806) Resensitizes Relapsing Tumors to RAS Inhibition.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 86 9 2026 May 04 2273-2285 Cancer Res
URL
Abstract Text Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. In this study, we identified persistent mTORC1 activity in preclinical KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability was targetable with the farnesyl transferase inhibitor darlifarnib (KO-2806), which blocks mTORC1 activation via RHEB while sparing mTORC2 to limit associated toxicities. The addition of KO-2806 to NSCLC or colorectal cancer tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on colorectal cancer tumor progression. Furthermore, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.KO-2806 salvages RAS inhibitor activity by controlling parallel mTORC1 in RAS inhibitor-resistant tumors in which vertical inhibition of MAPK is insufficient to restore sensitivity, providing a combination strategy for resistant patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS A146P head and neck squamous cell carcinoma sensitive Darlifarnib Preclinical - Pdx Actionable In a preclinical study, Darlifarnib (KO-2806) inhibited tumor growth in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring HRAS A146P (PMID: 41661652). 41661652
HRAS G13R head and neck squamous cell carcinoma sensitive Darlifarnib Preclinical - Pdx Actionable In a preclinical study, Darlifarnib (KO-2806) inhibited tumor growth more efficiently than Zarnestra (tipifarnib) and induced tumor regression in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring HRAS G13R (PMID: 41661652). 41661652