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Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Geeta Geeta Sharma1, Ines Mota2, Luca Mologni3,4

  • 1Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy. geeta.geeta@unimib.it.

Cancers
|March 3, 2018
PubMed

Insights

Anaplastic lymphoma kinase (ALK) inhibitors effectively treat ALK-rearranged cancers like non-small-cell lung cancer (NSCLC). However, drug resistance frequently emerges, necessitating new strategies to overcome treatment limitations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) is a key target in ALK-rearranged cancers, notably non-small-cell lung cancer (NSCLC).
  • ALK tyrosine kinase inhibitors (TKIs) like crizotinib were developed to target these malignancies.
  • Acquired resistance to ALK TKIs is a significant clinical challenge, limiting long-term patient benefit.

Purpose of the Study:

  • To review the physiological role and oncogenic function of ALK.
  • To provide an update on ALK inhibitors, including second and third-generation agents.
  • To summarize resistance mechanisms and explore therapeutic strategies to overcome TKI resistance.

Main Methods:

  • Literature review of ALK function, inhibitors, and resistance mechanisms.
  • Analysis of clinical and preclinical data on ALK-targeted therapies.
  • Synthesis of information on emerging resistance pathways and novel therapeutic approaches.

Main Results:

  • ALK plays a critical role in normal development and cancer transformation.
  • Multiple generations of ALK TKIs have been developed, showing initial efficacy but eventual resistance.
  • Diverse resistance mechanisms, both intrinsic and acquired, have been identified.
  • Emerging resistance necessitates the development of next-generation inhibitors and combination strategies.

Conclusions:

  • Understanding ALK's role and resistance mechanisms is crucial for improving NSCLC treatment.
  • Novel therapeutic strategies are needed to overcome acquired resistance to ALK TKIs.
  • Continued research into ALK biology and drug development holds promise for better patient outcomes.
Keywords:
ALK inhibitorsanaplastic large-cell lymphoma (ALCL)anaplastic lymphoma kinase (ALK)non-small-cell lung cancer (NSCLC)resistance to ALK inhibitorstargeted therapiestyrosine kinase (TK)

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