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Nat Commun. 2017 Sep 4;8(1):410. doi: 10.1038/s41467-017-00450-6.

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.

Author information

1
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark.
2
Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, 08028, Barcelona, Spain.
3
Instituto Oncológico Dr. Rosell, University Hospital Sagrat Cor, 08029, Barcelona, Spain.
4
Pivotal, 28023, Madrid, Spain.
5
Instituto Oncológico Dr. Rosell, Quiron-Dexeus University Hospital, 08028, Barcelona, Spain.
6
Protein Research Group, Institute of Biochemistry and Molecular Biology, University of Southern Denmark, 5230, Odense, Denmark.
7
Phase I Unit, Rigshospitalet, 2100, Copenhagen, Denmark.
8
Department of Medical Oncology, Vall D´Hebron, 08035, Barcelona, Spain.
9
Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, CA, 94158, USA. trever.bivona@ucsf.edu.
10
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, USA. trever.bivona@ucsf.edu.
11
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark. hditzel@health.sdu.dk.
12
Department of Oncology, Odense University Hospital, 5000, Odense, Denmark. hditzel@health.sdu.dk.
13
Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916, Badalona, Spain.
14
Germans Trias i Pujol, Health Sciences Institute and Hospital, Campus Can Ruti, 08916, Badalona, Spain.

Abstract

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.

PMID:
28871105
PMCID:
PMC5583255
DOI:
10.1038/s41467-017-00450-6
[Indexed for MEDLINE]
Free PMC Article

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