Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

Imane Chaib, Niki Karachaliou, Sara Pilotto, Jordi Codony Servat, Xueting Cai, Xuefei Li, Ana Drozdowskyj, Carles Codony Servat, Jie Yang, Chunping Hu, Andres Felipe Cardona, Guillermo Lopez Vivanco, Alain Vergnenegre, Jose Miguel Sanchez, Mariano Provencio, Filippo de Marinis, Antonio Passaro, Peng Cao, Noemi Reguart, Charo Garcia CampeloCristina Teixido, Isabella Sperduti, Sonia Rodriguez, Chiara Lazzari, Alberto Verlicchi, Itziar de Aguirre, Cristina Queralt, Jia Wei, Roger Estrada, Raimon Puig de la Bellacasa, Jose Luis Ramirez, Kirstine Jacobsen, Henrik J. Ditzel, Mariacarmela Santarpia, Santiago Viteri, Miguel Angel Molina, Caicun Zhou, Peng Cao, Patrick C. Ma, Trever G. Bivona, Rafael Rosell

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P =. 001, and HR = 2.57, 95% CI = 1.30 to 5.09, P =. 007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume109
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

STAT3 Transcription Factor
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Proteins
Protein-Tyrosine Kinases
Confidence Intervals
Cell Line
Lung Neoplasms
Polymerase Chain Reaction
Therapeutics
Drug Interactions
Immunoblotting
Heterografts
Disease-Free Survival
Neoplasms
Cell Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chaib, I., Karachaliou, N., Pilotto, S., Codony Servat, J., Cai, X., Li, X., ... Rosell, R. (2017). Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC. Journal of the National Cancer Institute, 109(9). https://doi.org/10.1093/jnci/djx014
Chaib, Imane ; Karachaliou, Niki ; Pilotto, Sara ; Codony Servat, Jordi ; Cai, Xueting ; Li, Xuefei ; Drozdowskyj, Ana ; Servat, Carles Codony ; Yang, Jie ; Hu, Chunping ; Cardona, Andres Felipe ; Vivanco, Guillermo Lopez ; Vergnenegre, Alain ; Sanchez, Jose Miguel ; Provencio, Mariano ; de Marinis, Filippo ; Passaro, Antonio ; Cao, Peng ; Reguart, Noemi ; Campelo, Charo Garcia ; Teixido, Cristina ; Sperduti, Isabella ; Rodriguez, Sonia ; Lazzari, Chiara ; Verlicchi, Alberto ; de Aguirre, Itziar ; Queralt, Cristina ; Wei, Jia ; Estrada, Roger ; de la Bellacasa, Raimon Puig ; Ramirez, Jose Luis ; Jacobsen, Kirstine ; Ditzel, Henrik J. ; Santarpia, Mariacarmela ; Viteri, Santiago ; Molina, Miguel Angel ; Zhou, Caicun ; Cao, Peng ; Ma, Patrick C. ; Bivona, Trever G. ; Rosell, Rafael. / Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 9.
@article{8f2c08140a654196b036aa67fa795645,
title = "Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC",
abstract = "Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95{\%} confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95{\%} CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95{\%} CI = 1.54 to 5.93, P =. 001, and HR = 2.57, 95{\%} CI = 1.30 to 5.09, P =. 007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.",
author = "Imane Chaib and Niki Karachaliou and Sara Pilotto and {Codony Servat}, Jordi and Xueting Cai and Xuefei Li and Ana Drozdowskyj and Servat, {Carles Codony} and Jie Yang and Chunping Hu and Cardona, {Andres Felipe} and Vivanco, {Guillermo Lopez} and Alain Vergnenegre and Sanchez, {Jose Miguel} and Mariano Provencio and {de Marinis}, Filippo and Antonio Passaro and Peng Cao and Noemi Reguart and Campelo, {Charo Garcia} and Cristina Teixido and Isabella Sperduti and Sonia Rodriguez and Chiara Lazzari and Alberto Verlicchi and {de Aguirre}, Itziar and Cristina Queralt and Jia Wei and Roger Estrada and {de la Bellacasa}, {Raimon Puig} and Ramirez, {Jose Luis} and Kirstine Jacobsen and Ditzel, {Henrik J.} and Mariacarmela Santarpia and Santiago Viteri and Molina, {Miguel Angel} and Caicun Zhou and Peng Cao and Ma, {Patrick C.} and Bivona, {Trever G.} and Rafael Rosell",
year = "2017",
month = "9",
day = "1",
doi = "10.1093/jnci/djx014",
language = "English (US)",
volume = "109",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "9",

}

Chaib, I, Karachaliou, N, Pilotto, S, Codony Servat, J, Cai, X, Li, X, Drozdowskyj, A, Servat, CC, Yang, J, Hu, C, Cardona, AF, Vivanco, GL, Vergnenegre, A, Sanchez, JM, Provencio, M, de Marinis, F, Passaro, A, Cao, P, Reguart, N, Campelo, CG, Teixido, C, Sperduti, I, Rodriguez, S, Lazzari, C, Verlicchi, A, de Aguirre, I, Queralt, C, Wei, J, Estrada, R, de la Bellacasa, RP, Ramirez, JL, Jacobsen, K, Ditzel, HJ, Santarpia, M, Viteri, S, Molina, MA, Zhou, C, Cao, P, Ma, PC, Bivona, TG & Rosell, R 2017, 'Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC', Journal of the National Cancer Institute, vol. 109, no. 9. https://doi.org/10.1093/jnci/djx014

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC. / Chaib, Imane; Karachaliou, Niki; Pilotto, Sara; Codony Servat, Jordi; Cai, Xueting; Li, Xuefei; Drozdowskyj, Ana; Servat, Carles Codony; Yang, Jie; Hu, Chunping; Cardona, Andres Felipe; Vivanco, Guillermo Lopez; Vergnenegre, Alain; Sanchez, Jose Miguel; Provencio, Mariano; de Marinis, Filippo; Passaro, Antonio; Cao, Peng; Reguart, Noemi; Campelo, Charo Garcia; Teixido, Cristina; Sperduti, Isabella; Rodriguez, Sonia; Lazzari, Chiara; Verlicchi, Alberto; de Aguirre, Itziar; Queralt, Cristina; Wei, Jia; Estrada, Roger; de la Bellacasa, Raimon Puig; Ramirez, Jose Luis; Jacobsen, Kirstine; Ditzel, Henrik J.; Santarpia, Mariacarmela; Viteri, Santiago; Molina, Miguel Angel; Zhou, Caicun; Cao, Peng; Ma, Patrick C.; Bivona, Trever G.; Rosell, Rafael.

In: Journal of the National Cancer Institute, Vol. 109, No. 9, 01.09.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

AU - Chaib, Imane

AU - Karachaliou, Niki

AU - Pilotto, Sara

AU - Codony Servat, Jordi

AU - Cai, Xueting

AU - Li, Xuefei

AU - Drozdowskyj, Ana

AU - Servat, Carles Codony

AU - Yang, Jie

AU - Hu, Chunping

AU - Cardona, Andres Felipe

AU - Vivanco, Guillermo Lopez

AU - Vergnenegre, Alain

AU - Sanchez, Jose Miguel

AU - Provencio, Mariano

AU - de Marinis, Filippo

AU - Passaro, Antonio

AU - Cao, Peng

AU - Reguart, Noemi

AU - Campelo, Charo Garcia

AU - Teixido, Cristina

AU - Sperduti, Isabella

AU - Rodriguez, Sonia

AU - Lazzari, Chiara

AU - Verlicchi, Alberto

AU - de Aguirre, Itziar

AU - Queralt, Cristina

AU - Wei, Jia

AU - Estrada, Roger

AU - de la Bellacasa, Raimon Puig

AU - Ramirez, Jose Luis

AU - Jacobsen, Kirstine

AU - Ditzel, Henrik J.

AU - Santarpia, Mariacarmela

AU - Viteri, Santiago

AU - Molina, Miguel Angel

AU - Zhou, Caicun

AU - Cao, Peng

AU - Ma, Patrick C.

AU - Bivona, Trever G.

AU - Rosell, Rafael

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P =. 001, and HR = 2.57, 95% CI = 1.30 to 5.09, P =. 007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

AB - Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P =. 001, and HR = 2.57, 95% CI = 1.30 to 5.09, P =. 007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

UR - http://www.scopus.com/inward/record.url?scp=85017265055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017265055&partnerID=8YFLogxK

U2 - 10.1093/jnci/djx014

DO - 10.1093/jnci/djx014

M3 - Article

C2 - 28376152

AN - SCOPUS:85017265055

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 9

ER -