Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer

Cheng Ji, Li Zhang, Yan Cheng, Raj Patel, Hao Wu, Yi Zhang, Mian Wang, Shundong Ji, Chandra P. Belani, Jin Ming Yang, Xingcong Ren

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Abstract

Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
JournalCancer Biology and Therapy
Volume15
Issue number5
DOIs
StatePublished - May 2014

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Ji, C., Zhang, L., Cheng, Y., Patel, R., Wu, H., Zhang, Y., Wang, M., Ji, S., Belani, C. P., Yang, J. M., & Ren, X. (2014). Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. Cancer Biology and Therapy, 15(5), 570-577. https://doi.org/10.4161/cbt.28162