Irati Garmendia1,2, María J Pajares1,2,3,4, Francisco Hermida-Prado3,5, Daniel Ajona1,6,3,4, Cristina Bértolo1,3, Cristina Sainz1, Amaya Lavín1, Ana B Remírez1, Karmele Valencia1,6,3, Haritz Moreno1, Irene Ferrer3,7, Carmen Behrens8,9, Myriam Cuadrado3,10, Luis Paz-Ares3,7,11,12, Xosé R Bustelo3,10, Ignacio Gil-Bazo3,4,13, Daniel Alameda1, Fernando Lecanda1,2,3,4, Alfonso Calvo1,2,3,4, Enriqueta Felip14, Montse Sánchez-Céspedes15, Ignacio I Wistuba8,9, Rocio Granda-Diaz3,5, Juan Pablo Rodrigo3,5, Juana María García-Pedrero3,5, Ruben Pio1,6,3,4, Luis M Montuenga1,2,3,4, Jackeline Agorreta1,2,3,4. 1. Program in Solid Tumors, Center for Applied Medical Research, Pamplona, Spain. 2. Department of Pathology, Anatomy, and Physiology, School of Medicine and. 3. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain. 4. Navarra Health Research Institute, Pamplona, Spain. 5. Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain. 6. Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain. 7. Lung Cancer Clinical Research Unit and Centro Nacional de Investigaciones Oncológicas, Madrid, Spain. 8. Department of Translational Molecular Pathology and. 9. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 10. Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Salamanca, Spain. 11. Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. 12. Medical School, Universidad Complutense, Madrid, Spain. 13. Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain. 14. Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; and. 15. Cancer Epigenetics and Biology Program, Genes and Cancer Group, Bellvitge Biomedical Research Institute, Hospitalet de Llobregat, Barcelona, Spain.
Abstract
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 and genetic (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.
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 and genetic (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.
Entities:
Keywords:
Src family kinases; YES1; dasatinib; lung cancer; predictive biomarker