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

Department of Clinical Medicine

61 Citations (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.

Original language	English
Article number	410
Journal	Nature Communications
Volume	8
Number of pages	14
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-017-00450-6
Publication status	Published - 1 Dec 2017

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancerFinal published version, 1.87 MBLicence: 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, vol. 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.",

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AU - Jacobsen, Kirstine

AU - Bertran-Alamillo, Jordi

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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

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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.

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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

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DO - 10.1038/s41467-017-00450-6

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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

Keywords

UN SDGs

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