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Ref Type Journal Article
PMID (37743366)
Authors Miyazaki I, Odintsov I, Ishida K, Lui AJW, Kato M, Suzuki T, Zhang T, Wakayama K, Kurth RI, Cheng R, Fujita H, Delasos L, Vojnic M, Khodos I, Yamada Y, Ishizawa K, Mattar MS, Funabashi K, Chang Q, Ohkubo S, Yano W, Terada R, Giuliano C, Lu YC, Bonifacio A, Kunte S, Davare MA, Cheng EH, de Stanchina E, Lovati E, Iwasawa Y, Ladanyi M, Somwar R
Title Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
Journal Vol Issue Date Pages Journal Short Title
Nature cancer 4 9 2023 Sep 1345-1361 Nat Cancer
URL
Abstract Text RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

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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
RET E768Q missense unknown RET E768Q lies within the protein kinase domain of the Ret protein (UniProt.org). E768Q has been identified in the scientific literature (PMID: 37743366, PMID: 38754058), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET G736A missense unknown RET G736A lies within the protein kinase domain of the Ret protein (UniProt.org). G736A has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET I788N missense unknown RET I788N lies within the protein kinase domain of the Ret protein (UniProt.org). I788N has been associated with drug resistance in the context of RET fusions (PMID: 28615362, PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, May 2025). Y
RET L730Q missense unknown RET L730Q lies within the protein kinase domain of the Ret protein (UniProt.org). L730Q has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET L730R missense unknown RET L730R lies within the protein kinase domain of the Ret protein (UniProt.org). L730R has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET L760Q missense unknown RET L760Q lies within the protein kinase domain of the Ret protein (UniProt.org). L760Q has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET L772M missense unknown RET L772M lies within the protein kinase domain of the Ret protein (UniProt.org). L772M has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
RET M759I missense unknown RET M759I lies within the protein kinase domain of the Ret protein (UniProt.org). M759I has been identified in the scientific literature (PMID: 37743366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET M918T Advanced Solid Tumor sensitive Vepafestinib Preclinical - Cell culture Actionable In a preclinical study, Vepafestinib (TAS0953/HM06) inhibited proliferation of cells expressing RET M918T in culture (PMID: 37743366). 37743366
RET C634W medullary thyroid carcinoma sensitive Vepafestinib Preclinical - Cell culture Actionable In a preclinical study, Vepafestinib (TAS0953/HM06) inhibited proliferation of a medullary thyroid cancer cell line harboring RET C634W in culture (PMID: 37743366). 37743366