Ovarian cancer (OC) is a heterogeneous disease characterized by low incidence, affecting around 4 % of women, but with rapid progression and high mortality rate [
1]. Although many strategies have been developed to improve the treatment of OC, it is still the fifth leading cause of death in females with cancer. Patients with OC are often diagnosed late in the course of the disease because the symptoms are subtle and women frequently remain unaware of the disease until it reaches advanced stages [
2]. The standard treatment of OC involves cytoreductive surgery followed by platinum-based combination therapy. Although most patients respond to this therapy, the development of chemoresistance prevents long-lasting treatment for OC patients and only 40 % of patients survive 5 years after diagnosis with advanced disease [
3,
4]. Advances in understanding of the molecular basis of chemoresistance and inefficient apoptosis are of great importance for the development of targetted therapeutic approaches that might lead to better outcomes than conventional methods alone [
5].
One of the major causes for the development of drug resistance is faulty apoptosis, one cause of which is overexpression of anti-apoptotic members of Bcl-2 family [
6]. The contribution of Bcl-2 family proteins to the emergence of drug resistance has made them attractive targets for the development of new therapies to treat OC. The intrinsic apoptosis pathway is regulated by the Bcl-2 family of proteins. Bcl-2, Bcl-X
L, Bcl-W, Mcl-1, and Bcl-2A1 act as inhibitors of this pathway by sequestering other pro-apoptotic family members [
7‐
9]. BH3-mimetics are a class of compound that bind to the apoptosis inhibitors, preventing them from binding the pro-apoptotic proteins and thereby potentiating apoptosis [
10]. In addition to overcoming drug resistance by promoting apoptosis, BH3 mimetics also induce autophagy. This is mediated through several mechanisms, including the liberation of the autophagy regulator Beclin from Bcl-2 family proteins [
11]. Autophagy has been linked to both cell survival and cell death and so BH3 mimetics may also modulate the effect of cytotoxic agents through this pathway. The most prominent drugs in this class are ABT-737, and its closely related orally bioavailable counterpart navitoclax (ABT-263). Both of these compounds can inhibit Bcl-2, Bcl-X
L and Bcl-W but not Mcl-1 [
12,
13]. We have shown that both these compounds can potentiate apoptosis induced by carboplatin using in vitro and xenograft models of ovarian cancer [
14,
15]. Although navitoclax has progressed to clinical trials and there have been initial signs of efficacy in some cancers, navitoclax also produced dose dependent thrombocytopenia by antagonizing the survival function of Bcl-X
L in platelets [
16]. As a result of this, ABT-199 (venetoclax) was developed by re-engineering navitoclax to produce a drug which selectively inhibits Bcl-2 protein but not Bcl-X
L. Clinical studies have demonstrated that ABT-199 does not cause significant thrombocytopenia and its efficacy is currently being evaluated in a number of cancer types [
17‐
19]. This led us to consider whether ABT-199 would also be effective in ovarian cancer. In our initial studies we noted that Bcl-2 is not widely expressed in ovarian cancer cell lines and this has also been observed in clinical samples [
20]. This is also confirmed by interrogation of the cancer genome atlas which reports Bcl-2 is amplified or mRNA upregulated in less than 3 % of cases [
21]. In contrast, the proportion of cases in which amplification or mRNA upregulation of Bcl-X
L (14 %), Bcl-W (12 %), or Mcl-1 (14 %) is observed is notably higher. This led us to question whether a Bcl-2 selective inhibitor would be of therapeutic use in a significant proportion of ovarian cancer patients. Instead, we hypothesized that a Bcl-X
L selective inhibitor would be preferable, although additional strategies would be necessary to overcome the likely ensuing thrombocytopenia. WEHI-539 is a recently described selective inhibitor of Bcl-X
L. We therefore compared the ability of ABT-199 and WEHI-539 to potentiate the activity of carboplatin. ABT-737, which antagonises Bcl-2, Bcl-X
L and Bcl-2, was included as a comparator. In several models, we found that WEHI-539, as well as ABT-737, augmented the activity of carboplatin but ABT-199 failed to do so. These observations suggest that compounds targeting Bcl-X
L will be of benefit in ovarian cancer, but novel strategies to minimize thrombocytopenia will be necessary.