The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib
Tao Shen, Xueqing Hu, Xuan Liu, Vivek Subbiah, Blaine H. M. Mooers, Jie Wu
Abstract
Recently Food and Drug Administration (FDA)-approved pralsetinib (BLU-667) and selpercatinib (LOXO-292) are RET-selective protein tyrosine kinase inhibitors for treating RET-altered cancers, but whether they have distinct activity was unknown. The L730V/I mutations at the roof of the solvent-front site of the RET kinase were identified as strongly resistant to pralsetinib but not to selpercatinib. Selpercatinib effectively inhibited these mutants and the KIF5B-RET(L730V/I) oncogene-driven tumors.
Topics & Concepts
Tyrosine kinaseMedicineCancer researchKinaseMutationProto-Oncogene Proteins c-retGeneticsBiologyInternal medicineGeneReceptorNeurotrophic factorsGlial cell line-derived neurotrophic factorLung Cancer Treatments and MutationsPI3K/AKT/mTOR signaling in cancerColorectal Cancer Treatments and Studies