TY - JOUR
T1 - YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib
AU - Garmendia, Irati
AU - Pajares, María J.
AU - Hermida-Prado, Francisco
AU - Ajona, Daniel
AU - Bértolo, Cristina
AU - Sainz, Cristina
AU - Lavín, Amaya
AU - Remírez, Ana B.
AU - Valencia, Karmele
AU - Moreno, Haritz
AU - Ferrer, Irene
AU - Behrens, Carmen
AU - Cuadrado, Myriam
AU - Paz-Ares, Luis
AU - Bustelo, Xosé R.
AU - Gil-Bazo, Ignacio
AU - Alameda, Daniel
AU - Lecanda, Fernando
AU - Calvo, Alfonso
AU - Felip, Enriqueta
AU - Sánchez-Céspedes, Montse
AU - Wistuba, Ignacio I.
AU - Granda-Diaz, Rocio
AU - Pablo Rodrigo, Juan
AU - García-Pedrero, Juana María
AU - Pio, Ruben
AU - Montuenga, Luis M.
AU - Agorreta, Jackeline
N1 - Funding Information:
Supported by Fundación para la Investigación Médica Aplicada (FIMA), Spanish Ministry of Economy and Innovation and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional grants 12/02040, PI13/00806, PI16/01821, PI16/00280, RTICC RD12/0036/0040, and SAF2015-6455-R; Centro de Investigación Biomédica en Red de Cáncer grants CB16/12/00390, CB16/12/00390, CB16/12/00442, and CB16/12/00443; Asociación Española Contra el Cáncer (AECC) Scientific Foundation grant GCB14-2170; Bristol-Myers Squibb (preclinical research agreement); AECC and a fellowship from the Basque Government (I.G.); the Castilla-León Government grant CSI049 U16 , the Ministry of Economy and Competitiveness grant SAF2015-64556-R , the Fundación Ramón Areces, Worldwide Cancer Research grant 14-1248 , and AECC Scientific Foundation grant GC16173472GARC (X.R.B.); and the Spanish Ministry of Science, Innovation and Universities (MCIU, RTI 2018-094507-B-100), La Caixa Foundation and Caja Navarra Foundation (F.L.).
Publisher Copyright:
© 2019 by the American Thoracic Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological andgenetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.
AB - Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological andgenetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.
KW - Dasatinib
KW - Lung cancer
KW - Predictive biomarker
KW - Src family kinases
KW - YES1
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U2 - 10.1164/rccm.201807-1292OC
DO - 10.1164/rccm.201807-1292OC
M3 - Article
C2 - 31166114
AN - SCOPUS:85072747188
SN - 1073-449X
VL - 200
SP - 888
EP - 899
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 7
ER -