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 Jørn Ditzel, Rafael Rosell

    116 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftNature Communications
    Vol/bind8
    Udgave nummer1
    Sider (fra-til)e410
    ISSN2041-1722
    DOI
    StatusUdgivet - 4 sep. 2017

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