Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

Kirstine Jacobsen, Jordi Bertran-Alamillo, Miguel Angel Molina, Cristina Teixidó, Niki Karachaliou, Martin Haar Pedersen, Josep Castellví, Mónica Garzón, Carles Codony-Servat, Jordi Codony-Servat, Ana Giménez-Capitán, Ana Drozdowskyj, Santiago Viteri, Martin R. Larsen, Ulrik Lassen, Enriqueta Felip, Trever G. Bivona (), Henrik J. Ditzel () and Rafael Rosell
Additional contact information
Kirstine Jacobsen: University of Southern Denmark
Jordi Bertran-Alamillo: Quiron Dexeus University Hospital
Miguel Angel Molina: Quiron Dexeus University Hospital
Cristina Teixidó: Quiron Dexeus University Hospital
Niki Karachaliou: University Hospital Sagrat Cor
Martin Haar Pedersen: University of Southern Denmark
Josep Castellví: Quiron Dexeus University Hospital
Mónica Garzón: Quiron Dexeus University Hospital
Carles Codony-Servat: Quiron Dexeus University Hospital
Jordi Codony-Servat: Quiron Dexeus University Hospital
Ana Giménez-Capitán: Quiron Dexeus University Hospital
Ana Drozdowskyj: Pivotal
Santiago Viteri: Quiron-Dexeus University Hospital
Martin R. Larsen: University of Southern Denmark
Ulrik Lassen: Phase I Unit, Rigshospitalet
Enriqueta Felip: Vall D´Hebron
Trever G. Bivona: University of California
Henrik J. Ditzel: University of Southern Denmark
Rafael Rosell: Quiron Dexeus University Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00450-6

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