Oncotarget

Research Papers:

Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma

Matthew J. Martin _, Cath Eberlein, Molly Taylor, Susan Ashton, David Robinson and Darren Cross

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Oncotarget. 2016; 7:86313-86325. https://doi.org/10.18632/oncotarget.13388

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Abstract

Matthew J. Martin1,2, Cath Eberlein1, Molly Taylor1,2, Susan Ashton1, David Robinson1,2, Darren Cross1,2

1AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom

2AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, United Kingdom

Correspondence to:

Matthew J. Martin, email: [email protected]

Keywords: non-small cell lung cancer, signal transduction, drug resistance, metabolism, pre-clinical models of drug efficacy

Received: March 30, 2016     Accepted: October 31, 2016     Published: November 16, 2016

ABSTRACT

Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment. However experience with targeted therapies suggests that acquired resistance may emerge. Thus there is a need to characterize resistance mechanisms and to devise ways to prevent, delay or overcome osimertinib resistance. We show here that osimertinib suppresses glycolysis in parental EGFR-mutant lung adenocarcinoma lines, but has not in osimertinib-resistant cell lines. Critically, we show osimertinib treatment induces a strict dependence on mitochondrial oxidative phosphorylation (OxPhos), as OxPhos inhibitors significantly delay the long-term development of osimertinib resistance in osimertinib-sensitive lines. Accordingly, growth conditions which promote a less glycolytic phenotype confer a degree of osimertinib resistance. Our data support a model in which the combination of osimertinib and OxPhos inhibitors can delay or prevent resistance in osimertinib-naïve tumour cells, and represents a novel strategy that warrants further pre-clinical investigation.


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