Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC
Chaib, Imane (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Karachaliou, Niki (Instituto Oncológico Dr. Rosell, Institut Universitari Quirón-Dexeus)
Pilotto, Sara (Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona)
Codony-Servat, Jordi (Pangaea Biotech, Laboratory of Molecular Biology)
Cai, Xueting (Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine)
Li, Xuefei (Shangai Pulmonary Hospital, Tongji University School of Medicine, Shangai)
Drozdowskyj, Ana (Pivotal, Madrid)
Codony Servat, Carles (Pangaea Biotech, Laboratory of Molecular Biology)
Yang, Jie (Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine)
Hu, Chunping (Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine)
Cardona Zorrilla, Andrés Felipe (Clinica del Country, Bogotá)
Lopez Vivanco, Guillermo (Hospital Universitario de Cruces (Barakaldo, País Basc))
Vergnenegre, Alain (Service de Pathologie Respiratoire et d'Allergologie, CHU, Limoges France)
Sanchez, Jose Miguel (Hospital Universitario de la Princesa (Madrid))
Provencio, Mariano (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Marinis, Filippo de (Hospital Universitario de Cruces (Barakaldo, País Basc))
Passaro, Antonio (Hospital Universitario de Cruces (Barakaldo, País Basc))
Carcereny, Enric (Service de Pathologie Respiratoire et d'Allergologie, CHU, Limoges France)
Reguart, Noemi (Hospital Clínic i Provincial de Barcelona)
Garcia Campelo, Charo (Hospital Universitario de la Princesa (Madrid))
Teixidó, Cristina (Pangaea Biotech, Laboratory of Molecular Biology)
Sperduti, Isabella (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Rodriguez, Sonia (Pangaea Biotech, Laboratory of Molecular Biology)
Lavazzi, Chiara (Hospital Universitario de Cruces (Barakaldo, País Basc))
Verlicchi, Alberto (Hospital Clínic i Provincial de Barcelona)
Aguirre, Itziar de (Institut Germans Trias i Pujol)
Queralt, C (Institut Germans Trias i Pujol)
Wei, Jia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Estrada-Tejedor, Roger (WVU Cancer Institute, West Virginia University, Morgantown, WV, USA)
Puig de la Bellacasa, Raimon (WVU Cancer Institute, West Virginia University, Morgantown, WV, USA)
Ramirez, Jose Luis (Institut Germans Trias i Pujol)
Jacobson, Kirstine (WV Clinical and Translational Science Institute, Morgantown, WV, USA)
Ditzel, Henrik J. (WV Clinical and Translational Science Institute, Morgantown, WV, USA)
Santarpia, Mariacarmela (UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA)
Viteri, Santiago (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Molina, Miguel Angel (Pangaea Biotech, Laboratory of Molecular Biology)
Zhou, Caicun (Shangai Pulmonary Hospital, Tongji University School of Medicine, Shangai)
Cao, Peng (Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China)
Ma, Patrick C. (WVU Cancer Institute, West Virginia University, Morgantown, WV, USA)
Bivona, Trever (UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA)
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Data:	2017
Resum:	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 (n¼4 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] ¼ 0. 54 to 0. 63) for the PC-9 and 0. 59 (95% CI¼0. 54 to 0. 63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] ¼ 3. 02, 95% CI¼1. 54 to 5. 93, P ¼ . 001, and HR¼2. 57, 95% CI¼1. 30 to 5. 09, P ¼ . 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.
Ajuts:	Ministerio de Economía y Competitividad RTICC/RD12-0036-0072
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of the National Cancer Institute, Vol. 109 (september 2017) , p. 1-12, ISSN 1460-2105

12 p, 1.4 MB

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