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; Rafael Rosell

doi:10.1038/s41467-017-00450-6

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, Rafael Rosell

Institut for Klinisk Medicin

61 Citationer (Scopus)

46 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	410
Tidsskrift	Nature Communications
Vol/bind	8
Antal sider	14
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-017-00450-6
Status	Udgivet - 1 dec. 2017

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10.1038/s41467-017-00450-6Licens: CC BY

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancerForlagets udgivne version, 1,87 MBLicens: CC BY

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Jacobsen, K., Bertran-Alamillo, J., Molina, M. A., Teixidó, C., Karachaliou, N., Pedersen, M. H., Castellví, J., Garzón, M., Codony-Servat, C., Codony-Servat, J., Giménez-Capitán, A., Drozdowskyj, A., Viteri, S., Larsen, M. R., Lassen, U., Felip, E., Bivona, T. G., Ditzel, H. J., & Rosell, R. (2017). Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nature Communications, 8, [410]. https://doi.org/10.1038/s41467-017-00450-6

Jacobsen, K, Bertran-Alamillo, J, Molina, MA, Teixidó, C, Karachaliou, N, Pedersen, MH, Castellví, J, Garzón, M, Codony-Servat, C, Codony-Servat, J, Giménez-Capitán, A, Drozdowskyj, A, Viteri, S, Larsen, MR, Lassen, U, Felip, E, Bivona, TG, Ditzel, HJ & Rosell, R 2017, 'Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer', Nature Communications, bind 8, 410. https://doi.org/10.1038/s41467-017-00450-6

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title = "Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer",

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.",

keywords = "Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung/drug therapy, Cell Line, Tumor, DNA Mutational Analysis, Drug Resistance, Neoplasm, Enzyme Activation, Female, Humans, Lung Neoplasms/drug therapy, Mice, Mice, SCID, Mutation, Neoplasm Transplantation, Proteomics, Proto-Oncogene Proteins c-akt/metabolism, Receptor, Epidermal Growth Factor/antagonists & inhibitors, Signal Transduction",

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T1 - Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

AU - Jacobsen, Kirstine

AU - Bertran-Alamillo, Jordi

AU - Molina, Miguel Angel

AU - Teixidó, Cristina

AU - Karachaliou, Niki

AU - Pedersen, Martin Haar

AU - Castellví, Josep

AU - Garzón, Mónica

AU - Codony-Servat, Carles

AU - Codony-Servat, Jordi

AU - Giménez-Capitán, Ana

AU - Drozdowskyj, Ana

AU - Viteri, Santiago

AU - Larsen, Martin R

AU - Lassen, Ulrik

AU - Felip, Enriqueta

AU - Bivona, Trever G

AU - Ditzel, Henrik J

AU - Rosell, Rafael

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Cell Line, Tumor

KW - DNA Mutational Analysis

KW - Drug Resistance, Neoplasm

KW - Enzyme Activation

KW - Female

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Mice

KW - Mice, SCID

KW - Mutation

KW - Neoplasm Transplantation

KW - Proteomics

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Receptor, Epidermal Growth Factor/antagonists & inhibitors

KW - Signal Transduction

U2 - 10.1038/s41467-017-00450-6

DO - 10.1038/s41467-017-00450-6

M3 - Journal article

C2 - 28871105

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 410

ER -

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

Abstract

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