Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Autophagy. 2017 Mar 4;13(3):608-624. doi: 10.1080/15548627.2016.1271512. Epub 2017 Jan 5.

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: MAPK/JNK; PDX; autophagy; endometrial cancer; kinase; lysosomes; sorafenib; targeted therapy.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Autophagy* / drug effects
  • Cell Line, Tumor
  • Disease Progression
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / enzymology
  • Endometrial Neoplasms / pathology*
  • Endometrial Neoplasms / ultrastructure
  • Endoplasmic Reticulum Stress / drug effects
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Targeted Therapy*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use
  • Sorafenib
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib
  • Mitogen-Activated Protein Kinases