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Erschienen in: Journal of Cancer Research and Clinical Oncology 4/2015

01.04.2015 | Original Article - Cancer Research

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

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

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 4/2015

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Abstract

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.

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.

Conclusions

These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.
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Metadaten
Titel
Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines
verfasst von
William S. Holland
Danielle C. Chinn
Primo N. Lara Jr.
David R. Gandara
Philip C. Mack
Publikationsdatum
01.04.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 4/2015
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-014-1855-4

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