LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress

Landon J. Inge, Jacqueline M. Friel, Amanda L. Richer, Aaron J. Fowler, Timothy Whitsett, Michael A. Smith, Nhan Tran, Ross M. Bremner

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations in the LKB1 tumor suppressor are common in NSCLC. Genetic and mechanistic analysis has defined LKB1-deficient NSCLC tumors as a phenotypically distinct subpopulation of NSCLC with potential avenues for therapeutic gain. In expanding on previous work indicating hypersensitivity of LKB1-deficient NSCLC cells to 2-deoxy-D-glucose (2DG), we find that 2DG has in vivo efficacy in LKB1-deficient NSCLC using transgenic murine models of NSCLC. Deciphering of the molecular mechanisms behind this phenotype reveals that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological compounds that aggravate ER stress. In comparison to NSCLC cells with functional LKB1, treatment of NSCLC cells lacking LKB1 with the ER stress activators (ERSA), tunicamycin, brefeldin A or 2DG, resulted in aggravation of ER stress, increased cytotoxicity, and evidence of ER stress-mediated cell death. Based upon these findings, we suggest that ERSAs represent a potential treatment avenue for NSCLC patients whose tumors are deficient in LKB1.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalCancer Letters
Volume352
Issue number2
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

Fingerprint

Non-Small Cell Lung Carcinoma
Pharmacology
Deoxyglucose
Brefeldin A
Therapeutics
Tunicamycin
Neoplasms
Hypersensitivity
Cell Death
Survival Rate
Phenotype
Mutation

Keywords

  • ER stress
  • LKB1
  • Lung cancer
  • Treatment
  • UPR

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inge, L. J., Friel, J. M., Richer, A. L., Fowler, A. J., Whitsett, T., Smith, M. A., ... Bremner, R. M. (2014). LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. Cancer Letters, 352(2), 187-195. https://doi.org/10.1016/j.canlet.2014.06.011

LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. / Inge, Landon J.; Friel, Jacqueline M.; Richer, Amanda L.; Fowler, Aaron J.; Whitsett, Timothy; Smith, Michael A.; Tran, Nhan; Bremner, Ross M.

In: Cancer Letters, Vol. 352, No. 2, 01.10.2014, p. 187-195.

Research output: Contribution to journalArticle

Inge, LJ, Friel, JM, Richer, AL, Fowler, AJ, Whitsett, T, Smith, MA, Tran, N & Bremner, RM 2014, 'LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress', Cancer Letters, vol. 352, no. 2, pp. 187-195. https://doi.org/10.1016/j.canlet.2014.06.011
Inge, Landon J. ; Friel, Jacqueline M. ; Richer, Amanda L. ; Fowler, Aaron J. ; Whitsett, Timothy ; Smith, Michael A. ; Tran, Nhan ; Bremner, Ross M. / LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. In: Cancer Letters. 2014 ; Vol. 352, No. 2. pp. 187-195.
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