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Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer

Ryohei Yoshida1, Takaaki Sasaki1, Yoshinori Minami1

  • 1Respiratory Center, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.

International Journal of Oncology
|October 20, 2017
PubMed

Insights

Targeting Src signaling overcomes resistance to anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer (NSCLC). Combining ALK and Src inhibitors effectively inhibits tumor growth in preclinical models, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in 3-5% of non-small cell lung cancer (NSCLC).
  • While ALK inhibitors (e.g., crizotinib, alectinib, ceritinib) are effective, acquired resistance is a significant clinical challenge.
  • Understanding resistance mechanisms is crucial for developing improved therapeutic strategies for ALK-NSCLC.

Purpose of the Study:

  • To investigate the intracellular signaling alterations driving resistance to ALK inhibitors in NSCLC.
  • To identify novel therapeutic targets for overcoming acquired resistance to ALK-targeted therapies.
  • To evaluate the efficacy of combination therapy targeting both ALK and identified resistance pathways.

Main Methods:

  • Utilized iTRAQ quantitative mass spectrometry to analyze proteomic changes in ALK inhibitor-resistant NSCLC cell lines.
  • Employed phosphor-receptor tyrosine kinase arrays to assess signaling pathway activation.
  • Tested combination treatment of ALK and Src inhibitors in vitro and in mouse xenograft models.

Main Results:

  • Src signaling was identified as a key mechanism of acquired resistance to alectinib.
  • Combination therapy with ALK and Src inhibitors demonstrated significant efficacy in inhibiting the growth of resistant NSCLC cells in vitro and in vivo.
  • Inhibition of Src effectively blocked phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling in resistant cells.
  • Combined ALK and Src inhibition also showed efficacy against NSCLC cell lines resistant to other ALK inhibitors, including ceritinib and lorlatinib.

Conclusions:

  • Targeting Src signaling represents a promising strategy to overcome acquired resistance to ALK inhibitors in NSCLC.
  • Combination therapy targeting ALK and Src pathways offers a potential new treatment approach for patients with resistant ALK-NSCLC.
  • Further clinical investigation of combined ALK and Src inhibition is warranted for managing advanced ALK-NSCLC.

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