Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations
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Published:2023-09-21
Issue:9
Volume:4
Page:1345-1361
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ISSN:2662-1347
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Container-title:Nature Cancer
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language:en
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Short-container-title:Nat Cancer
Author:
Miyazaki IsaoORCID, Odintsov Igor, Ishida Keiji, Lui Allan J. W.ORCID, Kato MasanoriORCID, Suzuki Tatsuya, Zhang Tom, Wakayama Kentaro, Kurth Renate I., Cheng Ryan, Fujita Hidenori, Delasos Lukas, Vojnic Morana, Khodos Inna, Yamada Yukari, Ishizawa Kota, Mattar Marissa S., Funabashi Kaoru, Chang Qing, Ohkubo Shuichi, Yano Wakako, Terada Ryuichiro, Giuliano ClaudioORCID, Lu Yue Christine, Bonifacio Annalisa, Kunte Siddharth, Davare Monika A.ORCID, Cheng Emily H.ORCID, de Stanchina Elisa, Lovati Emanuela, Iwasawa Yoshikazu, Ladanyi Marc, Somwar RomelORCID
Abstract
AbstractRET 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute Helsinn Healthcare, SA
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference60 articles.
1. Takahashi, M., Ritz, J. & Cooper, G. M. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42, 581–588 (1985). 2. Qian, Y. et al. KIF5B–RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer. Mol. Cancer 13, 176 (2014). 3. Takeuchi, K. et al. RET, ROS1 and ALK fusions in lung cancer. Nat. Med. 18, 378–381 (2012). 4. Pasini, A. et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene 15, 393–402 (1997). 5. Yang, S. R. et al. A performance comparison of commonly used assays to detect RET fusions. Clin. Cancer Res. 27, 1316–1328 (2021).
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