Diagnostics, therapeutics and RET inhibitor resistance for RET fusion-positive non-small cell lung cancers and future perspectives

Cancer Treat Rev. 2021 May;96:102153. doi: 10.1016/j.ctrv.2021.102153. Epub 2021 Jan 16.


Selective RET inhibitors is the current hot topic, making multikinase inhibitors a thing of the past. However, the limitation of various test approaches, coupled with lack of knowledge of acquired resistance mechanisms, and specific patient groups that bear special consideration, remains a challenge. Herein, we outline utility of various diagnostic techniques, provide evidence to guide management of RET-fusion-positive Non-Small Cell Lung Cancer (NSCLC) patients, including specific patient groups, such as EGFR-mutant NSCLC patients who acquired RET fusions after resisting EGFR TKIs, and offer a compendium of mechanisms of acquired resistance to RET targeted therapies. This review further provides a list of ongoing clinical trials and summarizes perspectives to guide future development of drugs and trials for this population.

Keywords: Acquired resistance; Molecular profiling; Multikinase inhibitor; Non-small cell lung cancer (NSCLC); RET fusion; Selective tyrosine kinase inhibitor.

Publication types

  • Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung / diagnosis*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Drug Resistance, Neoplasm
  • Female
  • Gene Fusion
  • Humans
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-ret / genetics*


  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-ret
  • RET protein, human