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.

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…In the same vein, JNK also can modulate resistance to 5-fluorouracil (5-FU) in CRC by enhancing BCL2 phosphorylation and autophagy, which protect against 5-FU induced apoptosis [85]. Such modulatory effects of JNK on responses to chemotherapies and targeted therapies were also observed in gastric cancer [86], hepatocellular carcinoma [87], head and neck cancer [88], endometrial cancer [89], and ovarian cancer [90]. An interesting finding in this context is that JNK signaling seems specifically important for the maintenance of cancer stem cells in different cancer types including pancreatic [91], endometrial [92], and ovarian cancer [93].…”

miR‑494‑3p promotes the progression of endometrial cancer by regulating the PTEN/PI3K/AKT pathway

“…Endometrial cancer (EC) is the fourth most prevalent and aggressive type of gynecological cancer, which has become a great threat against women's health (1,2). Annually, >280,000 women are diagnosed with EC worldwide; EC results in numerous cancer-associated mortalities (3). Unremitting efforts have been made to develop effective methods for treating EC in the past decades.…”

Scutellarin induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT Signaling Pathways in vitro and in vivo

“…Microtubule-associated protein light chain 3 (LC3), an excellent marker of autophagy, is widely used for monitoring autophagy 26 . During autophagy induction, the transition of the non-lipidated form of LC3 (LC3-I) to the lipidated form of LC3 (LC3-II) is indispensable 27 . Thus, the increase of LC3-II level or LC3-II/LC3-I ratio specifically signifies the induction of autophagy.…”