Related Experiment Video

Updated: Sep 29, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Published on: June 26, 2019

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The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Ezra Y Rosen1, Helen H Won2,3, Youyun Zheng4

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature Communications
|March 19, 2022
PubMed

Insights

Selpercatinib effectively treats RET-driven cancers. Acquired resistance emerges through MAPK pathway reactivation, often via secondary mutations or alternative drivers, necessitating combination therapies for sustained response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Selpercatinib is a highly selective RET inhibitor with established efficacy in RET-driven cancers.
  • Understanding resistance mechanisms is crucial for optimizing long-term treatment outcomes.

Purpose of the Study:

  • To characterize the molecular determinants of response and resistance to selpercatinib.
  • To identify mechanisms driving acquired resistance to RET-targeted therapy.

Main Methods:

  • Genomic profiling of tumors before and after treatment.
  • Analysis of molecular alterations associated with treatment response and resistance.

Main Results:

  • Pre-treatment genomic landscape minimally impacts treatment response, except for rare RAS-mediated primary resistance.
  • Acquired resistance is primarily driven by MAPK pathway reactivation through secondary RET mutations or MET amplifications.
  • Alternative mitogenic drivers in RET-wildtype populations can also emerge under treatment pressure.
  • Polyclonal resistance, involving multiple distinct mechanisms within the same patient, is frequently observed.

Conclusions:

  • Acquired resistance to selpercatinib is complex and often involves MAPK pathway reactivation.
  • Sequential RET-directed therapy may necessitate combination strategies targeting alternative MAPK effectors.
  • Prospective characterization of tumors at progression is essential for guiding subsequent treatment decisions.

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