Drug resistance to
chemotherapy occurs in many
ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new
therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a
cisplatin-resistant A2780-cis
ovarian cancer cell line, 38 active compounds with IC50s under 1 μM suppressed the growth of
cisplatin-resistant
ovarian cancer cells. Among these confirmed compounds,
CUDC-101,
OSU-03012,
oligomycin A,
VE-821, or Torin2 in a combination with
cisplatin restored
cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295,
SNX-5422,
AT-13387, and
PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming
cisplatin resistance in these cells is mediated by the inhibition of
epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of
cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR
mRNA reduced
cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for
cisplatin-resistant
ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and
drug combinations against drug-resistant
cancer cells.