Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer |
| |
Authors: | Núria Eritja Bo-Juen Chen Ruth Rodríguez-Barrueco Maria Santacana Sònia Gatius August Vidal |
| |
Institution: | 1. Department of Basic Sciences, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4, Lleida, Spain;2. Department of Pathology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida/Hospital Universitari Arnau de Vilanova, Lleida, Spain;3. New York Genome Center, New York, NY, USA;4. Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne, UK;5. Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain |
| |
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. |
| |
Keywords: | autophagy endometrial cancer kinase lysosomes MAPK/JNK PDX sorafenib targeted therapy |
|
|