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ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Christabel Wilson1, Mhairi Nimick1, Hayley Nehoff1

  • 1Department of Pharmacology & Toxicology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.

Scientific Reports
|October 26, 2017
PubMed

Insights

Investigating Insulin-like Growth Factor 1 Receptor (IGF-1R) in ALK-positive lung cancer reveals it as a druggable target. Combination therapy with ALK and IGF-1R inhibitors shows synergistic effects, even in resistant cells.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Anaplastic Lymphoma Kinase (ALK) positive non-small cell lung cancer (NSCLC) shows initial response to ALK inhibitors like crizotinib.
  • Acquired drug resistance to ALK inhibitors typically develops within a year, necessitating alternative therapeutic strategies.

Purpose of the Study:

  • To determine if Insulin-like Growth Factor 1 Receptor (IGF-1R) represents an independent, druggable target in ALK-positive NSCLC cells.
  • To evaluate the efficacy of combined ALK and IGF-1R inhibition in both drug-sensitive and drug-resistant ALK-positive NSCLC models.

Main Methods:

  • Treatment of ALK-positive NSCLC cells with ALK inhibitors (e.g., crizotinib) and IGF-1R inhibitors, both individually and in combination.
  • Assessment of cytotoxic effects and drug resistance profiles in both initial and acquired resistance settings.
  • Evaluation of treatment synergy and additivity.

Main Results:

  • Combination therapy of ALK and IGF-1R inhibitors demonstrated synergistic cytotoxicity against ALK-positive NSCLC cells.
  • This synergistic effect persisted for at least 12 days post-crizotinib initiation.
  • Cells acquired resistance to crizotinib did not develop cross-resistance to IGF-1R inhibition; combination therapy showed additive effects in resistant cells.

Conclusions:

  • IGF-1R is confirmed as an independent druggable target in ALK-positive lung cancer.
  • Combination treatment targeting both ALK and IGF-1R warrants clinical trials for ALK-positive NSCLC, including cases with acquired resistance.

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