Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

Abstract

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.

Keywords:

• ALK
• EGFR
• non-small-cell lung cancer
• TKI resistance
• TKIs

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• The use of rationally targeted agents has dramatically improved the prognosis of a subset of lung cancer patients whose tumors harbor somatically activated oncogenes, such as mutant EGFR and rearranged ALK.

• Unfortunately, almost all patients initially responding to EGFR or ALK tyrosine kinase inhibitors inevitably progress due to development of acquired resistance.

• Several mechanisms have been identified in tumor tissues after recurrence, including secondary mutations in the EGFR or ALK gene.

• Several novel targeted agents and rational combination regimens have been tested in the setting of acquired resistance. Among these, mutant-specific EGFR inhibitors and next-generation ALK inhibitors seem to be the most promising agents and are currently being tested in different treatment settings in Phase II and III trials.

• Much ongoing research is focusing on identifying unknown molecular abnormalities associated with resistance in oncogene-addicted cancer cell lines and in tumor samples from repeated biopsies, in order to develop and test new rational therapeutic strategies based on the underlying specific resistance mechanism.