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LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells

Oncogene volume 35, pages 856–866 (2016)Cite this article

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Abstract

The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20–30% of patients with non-small-cell lung cancer (NSCLC). Loss of LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a calcium/calmodulin-dependent protein kinase kinase 2 inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors.

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Acknowledgements

This work was supported by NIH P50 CA090949, DOD W81XWH-12-1-0383, NSF CBET-1105991, and by an award from Uniting Against Lung Cancer. Dr Joshua P. Fessel was also supported by NIH K08 HL121174. The authors thank Dr Changki Lee for his assistance with the animal experiments.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA

    Y M Whang, I A Trenary, R A Egnatchik & J D Young

  2. Division of Clinical Pharmacology, Department of Medicine, Center for Bone Biology, Vanderbilt University, Nashville, TN, USA

    S I Park

  3. Division of Allergy, Department of Medicine, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA

    J P Fessel

  4. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    J M Kaufman

  5. Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA

    D P Carbone

  6. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    J D Young

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Correspondence to J D Young.

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Whang, Y., Park, S., Trenary, I. et al. LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells. Oncogene 35, 856–866 (2016). https://doi.org/10.1038/onc.2015.140

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