title: Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma.
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.
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.|AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Martin
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Cath
authors.initials: C
authors.lastname: Eberlein
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.|AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Molly
authors.initials: M
authors.lastname: Taylor
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.|AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Robinson
authors.affiliation: AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.|AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
mesh_terms: D000178:Acrylamides; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000814:Aniline Compounds; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines
keywords: drug resistance; metabolism; non-small cell lung cancer; pre-clinical models of drug efficacy; signal transduction