PMID- 27861144
OWN - NLM
STAT- MEDLINE
DCOM- 20180222
LR  - 20220603
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 52
DP  - 2016 Dec 27
TI  - Inhibition of oxidative phosphorylation suppresses the development of osimertinib 
      resistance in a preclinical model of EGFR-driven lung adenocarcinoma.
PG  - 86313-86325
LID - 10.18632/oncotarget.13388 [doi]
AB  - 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-naive tumour cells, and represents a novel strategy that warrants 
      further pre-clinical investigation.
FAU - Martin, Matthew J
AU  - Martin MJ
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
AD  - AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, 
      United Kingdom.
FAU - Eberlein, Cath
AU  - Eberlein C
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
FAU - Taylor, Molly
AU  - Taylor M
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
AD  - AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, 
      United Kingdom.
FAU - Ashton, Susan
AU  - Ashton S
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
FAU - Robinson, David
AU  - Robinson D
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
AD  - AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, 
      United Kingdom.
FAU - Cross, Darren
AU  - Cross D
AD  - AstraZeneca Oncology, Innovative Medicines, Alderley Park, Macclesfield, 
      Cheshire, United Kingdom.
AD  - AstraZeneca Oncology, Innovative Medicines, CRUK Cambridge Institute, Cambridge, 
      United Kingdom.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Acrylamides)
RN  - 0 (Aniline Compounds)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 3C06JJ0Z2O (osimertinib)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Acrylamides
MH  - Adenocarcinoma/*drug therapy/pathology
MH  - Adenocarcinoma of Lung
MH  - Aniline Compounds
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - ErbB Receptors/*antagonists & inhibitors/genetics
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/pathology
MH  - Oxidative Phosphorylation/*drug effects
MH  - Piperazines/*pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
PMC - PMC5349916
OTO - NOTNLM
OT  - drug resistance
OT  - metabolism
OT  - non-small cell lung cancer
OT  - pre-clinical models of drug efficacy
OT  - signal transduction
COIS- CONFLICTS OF INTEREST All authors are current or former employees of AstraZeneca.
EDAT- 2016/11/20 06:00
MHDA- 2018/02/23 06:00
PMCR- 2016/12/27
CRDT- 2016/11/19 06:00
PHST- 2016/03/30 00:00 [received]
PHST- 2016/10/31 00:00 [accepted]
PHST- 2016/11/20 06:00 [pubmed]
PHST- 2018/02/23 06:00 [medline]
PHST- 2016/11/19 06:00 [entrez]
PHST- 2016/12/27 00:00 [pmc-release]
AID - 13388 [pii]
AID - 10.18632/oncotarget.13388 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Dec 27;7(52):86313-86325. doi: 10.18632/oncotarget.13388.