Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: An ex vivo experiment in human serous ovarian carcinoma

Ovarian cancers are addicted to Bcl-x(L) and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-x(L) can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naive and had undergone surgery were prospectively exposed ex vivo to ABT-737carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value=0.019 by Fisher's test and sensitivity=93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737). What's new? While ABT-737 exhibits apoptotic activity as a single agent in a wide variety of cancer cells, in ovarian cancers Mcl-1 expression seemingly has to be down-regulated for ABT-737 to be effective. Here, using fresh patient ovarian tumor samples, the authors assessed the sensitivity of tumor nodes to ABT-737 combined with carboplatin, an indirect inhibitor of Mcl-1. ABT-737 showed promise as a monotherapy, with Bim acting as a robust predictive response factor. Bim's predictive value was strongly improved by the concomitant consideration of P-Erk and Mcl-1 expression levels, which provides an attractive strategy for the selection of patients in clinical trials.