Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines

William S. Holland, Danielle C. Chinn, Primo N Lara, David R Gandara, Philip Mack

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Results: The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested.

Purpose: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance.

Methods: The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance.

Conclusions: These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.

Original languageEnglish (US)
Pages (from-to)615-626
Number of pages12
JournalJournal of Cancer Research and Clinical Oncology
Volume141
Issue number4
DOIs
StatePublished - 2015

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Non-Small Cell Lung Carcinoma
Cell Line
Mitogen-Activated Protein Kinase Kinases
Erlotinib Hydrochloride
Receptor Protein-Tyrosine Kinases
Cell Cycle Checkpoints
Immunoblotting
Signal Transduction
Lung Neoplasms
Flow Cytometry
Cell Death
Phosphotransferases
Apoptosis
Mutation
Growth
MK 2206

Keywords

  • AKT
  • EGFR mutations
  • Erlotinib
  • HGF
  • NSCLC

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines. / Holland, William S.; Chinn, Danielle C.; Lara, Primo N; Gandara, David R; Mack, Philip.

In: Journal of Cancer Research and Clinical Oncology, Vol. 141, No. 4, 2015, p. 615-626.

Research output: Contribution to journalArticle

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