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Targeting USP11 for the treatment of platinum-resistant ovarian cancer


Platinum-resistant ovarian cancer has the lowest survival rate of all gynaecological cancers in the US and Europe. While patients initially respond well to platinum therapy, resistance will eventually occur leaving the patients with few treatment options. In order to identify new treatment paradigms, we performed a screen to identify deubiquitylating enzymes required for survival of platinum-resistant ovarian cancer. We identified USP11 as an essential enzyme for the growth of platinum-resistant cells but not platinum-sensitive tumour cells in an isogenic model derived from patient tumours, before or after development of resistance. In addition, USP11 depletion selectively prevented the growth of ovarian cancer cell lines rendered platinum-resistant in vitro. Given the importance of homologous recombination deficiencies (HRD) in ovarian cancer, the role played by USP11 in HRD tumours was also investigated in isogenic cell line models. USP11 depletion displayed synthetic lethality in isogenic HRD models such as BRCA2 or ATR supporting its previously identified functions in homologous recombination (Wiltshire et al., 2010; Schoenfeld et al., 2004). Progress towards the development of selective USP11 inhibitors for the treatment of platinum-resistant ovarian cancer or tumours bearing HRD will be presented; pharmacological inhibition of USP11 recapitulates the synthetic lethality phenotypes observed with siRNA in platinum-resistant ovarian cancer cells as well as in isogenic HRD backgrounds. Altogether, our findings strongly support the importance of USP11 as an attractive drug target for tumours with high unmet medical needs.
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