MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer

Abstract

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.

Secreted soluble factors from tumor-activated mesenchymal stromal cells confer platinum chemoresistance to ovarian cancer cells

“…The potential utilization of crizotinib, a c-MET inhibitor, is relevant to the finding that in 7-27% of OC cases, c-MET was overexpressed. Its activation was found related to poor prognosis in patients with high-grade serous ovarian cancer (HGSOC) [67]. In addition, our results corroborate previous finding showing synergistic activity of crizotinib and platinum compounds in animal models of OC [68,69].…”

Cancer Cells Haploinsufficient for ATM Are Sensitized to PARP Inhibitors by MET Inhibition

“…ATM haploinsufficiency is the feature that make cells overexpressing MET susceptible to the combined treatment even at low doses of the small molecule METi. Data shown here confirm that MET expression and activation are not sufficient to make MET overexpressing cells, such as ovarian cancer cells, susceptible to METi or to the combined treatment, in line with the report that no synergistic effects of the combined treatment with PARPi and METi were found in cell lines with BRCA1 or BRCA2 deficiency [ 40 ]. This agrees also with the recent report that increased MET protein expression was found in primary cultures of PARPi resistant high-grade serous ovarian carcinomas [ 41 ].…”

Ovarian cancer ascites confers platinum chemoresistance to ovarian cancer cells

“…Overexpression of c-MET was reported in 7–27 % of OC patients. Its activation was linked to a poor prognosis in individuals with high-grade serous ovarian cancer (HGSOC) [50] , lung, breast, stomach, and head and neck cancers. Treatment with crizotinib increased apoptosis and reduced cell proliferation in OC cell carcinomas with elevated levels of c-MET.…”