Ovarian Cancer Research Symposium: Role of Antiapoptotic Genes in Chemotherapy Resistance
Posted: Monday, October 1, 2018
Patients with high-grade serous ovarian cancer may benefit from therapeutic targeting of BCL-XL and MCL1, especially when combined with DNA-damaging agents, based on the results of pooled genomic screens presented at the 2018 Ovarian Cancer Research Symposium in Seattle. Elizabeth H. Stover, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues indicated that antiapoptotic proteins mediate resistance to drugs including cisplatin and paclitaxel. The conference was hosted by The Rivkin Center for Ovarian Cancer and the American Association for Cancer Research.
Using unbiased near genome–scale pooled overexpression and CRISPR/Cas9 knockout screens in two BRCA2-mutant cell lines, the investigators identified genes that promoted survival after treatment with cisplatin, paclitaxel, or combination therapy. The overexpression screen identified BCL-XL and BCL-W as the most common antiapoptotic genes mediating chemotherapy resistance. A second overexpression screen validated previous testing and identified other candidates as potential resistance genes.
Results suggested that overexpression of BCL-XL, BCL-W, BCL-2, or MCL1 may be linked to platinum and taxane resistance and reduced chemotherapy-induced cell death. The inhibition of BCL-XL, MCL1, or BCL2/BCL-XL significantly increased apoptosis in combination with cisplatin or paclitaxel. However, inhibiting BCL2 did not increase cell death. Furthermore, the associated overexpression of BCL-XL, BCL-W, or MCL1 overturned the sensitizing effect of antiapoptotic inhibitors.
“Our studies…support that BCL-XL and MCL1 may be therapeutic targets in [high-grade serous ovarian cancer], particularly I combination with DNA-damaging agents,” the investigators proposed.
