title: Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer.
abstract: Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Eritja
authors.affiliation: c New York Genome Center , New York , NY , USA.
authors.forename: Bo-Juen
authors.initials: BJ
authors.lastname: Chen
authors.affiliation: d Institute of Genetic Medicine, Newcastle University , Newcastle-Upon-Tyne , UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodríguez-Barrueco
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Gatius
authors.affiliation: e Department of Pathology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.affiliation: f Department of Gynecology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Martí
authors.affiliation: f Department of Gynecology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ponce
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Bergadà
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Andree
authors.initials: A
authors.lastname: Yeramian
authors.affiliation: g Department of Experimental Medicine , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8 , Lleida , Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Encinas
authors.affiliation: g Department of Experimental Medicine , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8 , Lleida , Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Ribera
authors.affiliation: e Department of Pathology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.|f Department of Gynecology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventós
authors.affiliation: h Department of Human and Molecular Genetics , Herbert Wertheim College of Medicine, Florida International University , Miami , FL , USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
authors.affiliation: i Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE) , Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.|e Department of Pathology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.|f Department of Gynecology , University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat , Barcelona , Catalonia , Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.|b Department of Pathology , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova , Lleida , Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.affiliation: d Institute of Genetic Medicine, Newcastle University , Newcastle-Upon-Tyne , UK.
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navàs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D020928:Mitogen-Activated Protein Kinases
keywords: MAPK/JNK; PDX; autophagy; endometrial cancer; kinase; lysosomes; sorafenib; targeted therapy