Reference Detail

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), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
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, Apr 2024).
RET	G810D	missense	unknown	RET G810D lies within the protein kinase domain of the Ret protein (UniProt.org). G810D 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, Apr 2024).
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, Aug 2024).	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, Apr 2024).
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, Apr 2024).
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, Apr 2024).
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, Apr 2024).
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, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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