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

Research output: Contribution to journalArticle

50 Citations (Scopus)

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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Autophagy
Lung Neoplasms
Drug Resistance
Chloroquine
Non-Small Cell Lung Carcinoma
crizotinib
Down-Regulation
Cell Line
Therapeutics
Pharmaceutical Preparations
Proteins

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., ... 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
Ji, Cheng ; Zhang, Li ; Cheng, Yan ; Patel, Raj ; Wu, Hao ; Zhang, Yi ; Wang, Mian ; Ji, Shundong ; Belani, Chandra P. ; Yang, Jin Ming ; Ren, Xingcong. / Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. In: Cancer Biology and Therapy. 2014 ; Vol. 15, No. 5. pp. 570-577.
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Ji, C, Zhang, L, Cheng, Y, Patel, R, Wu, H, Zhang, Y, Wang, M, Ji, S, Belani, CP, Yang, JM & Ren, X 2014, 'Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer', Cancer Biology and Therapy, vol. 15, no. 5, pp. 570-577. https://doi.org/10.4161/cbt.28162

Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. / Ji, Cheng; Zhang, Li; Cheng, Yan; Patel, Raj; Wu, Hao; Zhang, Yi; Wang, Mian; Ji, Shundong; Belani, Chandra P.; Yang, Jin Ming; Ren, Xingcong.

In: Cancer Biology and Therapy, Vol. 15, No. 5, 05.2014, p. 570-577.

Research output: Contribution to journalArticle

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AU - Ren, Xingcong

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