Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer

Abstract

Background: Epithelial ovarian cancer (EOC) is a highly lethal malignancy. Improvement in genetic characterization of EOC patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are protein tyrosine kinases (PTKs) whose role in EOC need to be better investigated. Methods: EOC genomic datasets are retrieved and analyzed. The biological and clinical significance of RET genomic aberrations in ovarian cancer context are investigated by a series of in vitro and in vivo experiments. Results: Epithelial ovarian cancer sequencing projects identify recurrent genomic RET missense mutations in 1.98% of patients, ranking as the top-five hit among the 100 receptor tyrosine kinases-encoding genes. RET mutants R693H and A750T show oncogenic transformation properties in NIH3T3 cells. Introduction of the RET mutants into human EOC cells increases RET signaling, cell viability, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. RET mutants significantly enhance the activation of RET and its downstream MAPK and AKT signaling pathway in ovarian cancer cells. Vandetanib, a clinical approved RET inhibitor, inhibits the cell viability and decreases the activation of RET-MAPK signaling pathways in EOC cells expressing oncogenic RET mutants. Conclusions: The discovery of RET pathogenic variants in the EOC patients, suggests a previously underestimated role for RET in EOC tumorigenesis. The identification of the gain-of-function RET mutations in EOC highlights the potential use of RET in targeted therapy to treat ovarian cancer patients.

SLC11A2: a promising biomarker and therapeutic target in ovarian cancer

“…Ovarian cancer remains the malignant tumor with the highest mortality rate among gynecological tumors 18 . Because the ovary is located in the deep pelvis 19 , ovarian cancer has no obvious symptoms, and most of the diagnosed patients are in the advanced stage (FIGO III-IV stage) 20 , and the ovarian is an abdominal organ with a rapid disease progression. According to statistics 21 , the 5-year survival rate of ovarian cancer is 76–93% for stage I, 60–74% for stage II, 23–41% for stage III, and 11% for stage IV.…”

RET signaling pathway and RET inhibitors in human cancer

“…In addition to pancreatic cancers, RET is altered in ~1.2% of ovarian cancers ( 41 ). Oncogenic RET variants have been recently identified in epithelial ovarian carcinomas, which were sensitive to treatment with vandetanib, an MKI with non-selective RET activity ( 199 ). However, additional studies are required to determine the therapeutic utility of RET inhibition in ovarian cancers.…”

Network controllability solutions for computational drug repurposing using genetic algorithms

“…Additionally, two other drugs targeting the same proteins are investigated for use in treating unspecified cancer types (LErafAON, XL281). Two of the other top controlling proteins, RET and MTCP1, are known to be significant in other types of cancer, such as ovarian cancer 32 , pancreatic cancer 33 , prostate cancer 34 or brain cancer 35 . Even more, there already exists an FDA-approved breast cancer drug targeting these proteins (selpercatinib), as well as several approved and investigational drugs used for treating other cancer types (ponatinib, sorafenib, sunitinib, cabozantinib, amuvatinib).…”