Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.

ABSTRACT:

Background

Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.

Patients and methods

Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-res

SUBMITTER: Subbiah V 

PROVIDER: S-EPMC7883646 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature