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Drug resistance in ALK-positiveNon-small cell lungcancer patients

Mengjia Qian1, Bijun Zhu1, Xiangdong Wang1

  • 1Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China.

Seminars in Cell & Developmental Biology
|October 4, 2016
PubMed

Insights

Anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) patients face resistance to targeted therapies. This review details resistance mechanisms, focusing on mutations, to guide optimal ALK inhibitor selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) accounts for 3-7% of cases.
  • Three generations of ALK inhibitors exist, but drug resistance remains a challenge.

Purpose of the Study:

  • To review the pathophysiology of ALK-positive NSCLC.
  • To discuss the role and resistance mechanisms of three generations of ALK inhibitors.
  • To analyze the structural and molecular basis of resistance to inform therapeutic decisions.

Main Methods:

  • Literature review of ALK-positive NSCLC pathophysiology.
  • Analysis of ALK inhibitor mechanisms and resistance pathways.
  • Examination of ALK protein structure and mutation impact.

Main Results:

  • Point mutations are the primary mechanism of secondary resistance to ALK inhibitors.
  • Different inhibitors are associated with specific resistance-conferring mutations.
  • Understanding ALK structure aids in predicting functional impact of mutations.

Conclusions:

  • Secondary resistance to ALK inhibitors in NSCLC is largely driven by point mutations.
  • Knowledge of resistance mechanisms and ALK structure is crucial for selecting effective therapies.
  • Optimizing ALK inhibitor selection can improve treatment outcomes for ALK-positive NSCLC patients.
Keywords:
ALKAlectinibCeritinibCrizotinibLorlatinibPoint mutation

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