Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer
| Autor: | Alberto Villanueva, Maria Santacana, Jordi Ponce, Sonia Gatius, Maria Dolores Martí, Nuria Eritja, Xavier Dolcet, Andree Yeramian, August Vidal, Laura Bergadà, Xavier Matias-Guiu, Jeff Boyd, Jaume Reventós, Ruth Rodriguez-Barrueco, Joan Muela Ribera, Mario Encinas, Bo-Juen Chen, David Llobet-Navas |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Kinase medicine.medical_treatment Cell Targeted therapy 0302 clinical medicine Endometrial cancer Molecular Targeted Therapy Sorafenib Endoplasmic Reticulum Stress targeted therapy medicine.anatomical_structure 030220 oncology & carcinogenesis Hepatocellular carcinoma endometrial cancer Disease Progression Female Mitogen-Activated Protein Kinases medicine.drug Niacinamide autophagy kinase Mice Nude Antineoplastic Agents MAPK/JNK Biology 03 medical and health sciences lysosomes Cell Line Tumor Autophagy medicine Animals Humans Molecular Biology PDX Phenylurea Compounds Cell Biology medicine.disease Xenograft Model Antitumor Assays Endometrial Neoplasms Enzyme Activation 030104 developmental biology Cancer research Clinical Research Paper Lysosomes |
| Zdroj: | Repositorio Abierto de la UdL Universitad de Lleida Autophagy Recercat. Dipósit de la Recerca de Catalunya instname |
| ISSN: | 1554-8635 1554-8627 |
| Popis: | 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. This work was supported by MINECO (SAF2016-80157-R), the Fondo de Investigaciones Sanitarias (PI10/00922, PI10/00604, PI13/01339 and PIE13–00022 (Oncoprofile)), Grant 2009SGR794 (Barcelona, Spain), Fundaci on Asociaci on Espa~nola Contra el C ancer (AECC-2011), AECC_- Barcelona and RETICS (RD12/0036/0013). DLN is recipient of a NURF scheme. The funders had no involvement in the study design, execution, analysis or interpretation of data and writing of the manuscript. |
| Databáze: | OpenAIRE |
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