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

Y. M. Whang, Serkin Park, I. A. Trenary, R. A. Egnatchik, J. P. Fessel, J. M. Kaufman, D. P. Carbone, J. D. Young

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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.

Original languageEnglish
Pages (from-to)856-866
Number of pages11
JournalOncogene
Volume35
Issue number7
DOIs
Publication statusPublished - 2016 Feb 18
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Whang, Y. M., Park, S., Trenary, I. A., Egnatchik, R. A., Fessel, J. P., Kaufman, J. M., Carbone, D. P., & Young, J. D. (2016). LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells. Oncogene, 35(7), 856-866. https://doi.org/10.1038/onc.2015.140