Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Shuang Xiang; Xiaoyun Lu

doi:10.1016/j.apsb.2023.11.010

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Acta Pharm Sin B. 2024 Feb;14(2):517-532. doi: 10.1016/j.apsb.2023.11.010. Epub 2023 Nov 8.

Authors

Shuang Xiang¹, Xiaoyun Lu¹

Affiliation

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.

Abstract

Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKA^G667C/A/S, homologous TRKC^G696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

Keywords: Clinical resistance; NTRK fusions; Selective type II inhibitors; TRK kinase; xDFG mutations.

Publication types

Review