The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Academic Article uri icon

Overview

abstract

  • The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.

authors

publication date

  • March 18, 2022

Research

keywords

  • Lung Neoplasms
  • Thyroid Neoplasms

Identity

PubMed Central ID

  • PMC8933489

Scopus Document Identifier

  • 85126697189

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2004088

PubMed ID

  • 35304457

Additional Document Info

volume

  • 13

issue

  • 1