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Abstract
Histone deacetylase (HDAC) inhibitors and proteasome inhibitors have been approved by the FDA for the treatment of multiple myeloma and lymphoma, respectively, but have not achieved similar activity as single agents in solid tumors. Preclinical studies have demonstrated the activity of the combination of an HDAC inhibitor and a proteasome inhibitor in a variety of tumor models. However, the mechanisms underlying sensitivity and resistance to this combination are not well-understood. This study explores the role of autophagy in adaptive resistance to dual HDAC and proteasome inhibition. Studies focus on ovarian and endometrial gynecologic cancers, two diseases with high mortality and a need for novel treatment approaches. We found that nanomolar concentrations of the proteasome inhibitor ixazomib and HDAC inhibitor romidepsin synergistically induce cell death in the majority of gynecologic cancer cells and patient-derived organoid (PDO) models created using endometrial and ovarian patient tumor tissue. However, some models were not sensitive to this combination, and mechanistic studies implicated autophagy as the main mediator of cell survival in the context of dual HDAC and proteasome inhibition. Whereas the combination of ixazomib and romidepsin reduces autophagy in sensitive gynecologic cancer models, autophagy is induced following drug treatment of resistant cells. Pharmacologic or genetic inhibition of autophagy in resistant cells reverses drug resistance as evidenced by an enhanced anti-tumor response both in vitro and in vivo. Taken together, our findings demonstrate a role for autophagic-mediated cell survival in proteasome inhibitor and HDAC inhibitor-resistant gynecologic cancer cells. These data reveal a new approach to overcome drug resistance by inhibiting the autophagy pathway.
Highlights
Endometrial and ovarian cancer are two of the most common gynecologic malignancies
We demonstrate that gynecologic cancer cell lines, xenografted animal models, and RESULTS The majority of endometrial and ovarian cancer patient-derived organoid (PDO) models and cell lines are sensitive to dual treatment with a proteasome inhibitor and Histone deacetylase (HDAC) inhibitor To understand the effect of ixazomib and romidepsin on cell viability, drug response assays were performed on 17 PDO models of endometrial and ovarian cancer from patient tumor tissues as well as three endometrial cancer PDX models (Table S1)
Similar results were obtained with other HDAC inhibitors and proteasome inhibitors (Fig. S1), indicating this effect is not specific to romidepsin and ixazomib
Summary
Endometrial and ovarian cancer are two of the most common gynecologic malignancies. These diseases combined lead to 25,000 deaths annually in the US [1]. Multiple clinical trials with proteasome and HDAC inhibitors are ongoing in solid tumors, some of which have shown promising results [21]. The combination of vorinostat with the proteasome inhibitor marizomib was tested in a Phase I clinical trial (NCT00667082) of advanced or recurrent solid tumors. The combination of vorinostat with bortezomib in patients with advanced solid tumors (NCT00227513) resulted in stable disease in most patients [23] This combination has not been yet tested in clinical trials of women with gynecologic malignancies. While preclinical studies have demonstrated the activity of HDAC and proteasome inhibitors in solid tumors [24,25,26], including our own work in gynecologic cancer cell lines [27], the mechanisms underlying sensitivity vs resistance to this combination are not well understood. We demonstrate that gynecologic cancer cell lines, xenografted animal models, and
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