Combination Of Letrozole Plus Abemaciclib Is Synergistic And Suppresses Tumor Growth In Ovarian And Endometrial Cancer Models

Background: Although aromatase inhibitors (AIs) including letrozole are effective for treating women with estrogen receptor positive (ER+) breast cancer, AI therapy demonstrates minimal clinical benefit in women with gynecological cancers, despite the high prevalence of ER positivity in endometrial and ovarian cancers. We hypothesized that combination treatment with abemaciclib (a small molecule inhibitor of CDK4/6) and letrozole could overcome intrinsic endocrine resistance in gynecological cancer models. Methods: We treated ER+, retinoblastoma (RB)-wildtype ovarian and endometrial cancer cell lines (SKOV3, Ishikawa) with letrozole, abemaciclib, or both concurrently. An RB-mutated ovarian cancer cell line (A2780) was used as a control due to its intrinsic resistance to CDK 4/6 inhibitor therapy. The drugs were combined at equipotent fixed molar ratio concentrations, serially diluted, and the effect on cell viability determined using the SRB assay. Calcusyn software was used to evaluate the dose-effect relationship of each drug alone or in combination, and a combination index (CI) value was calculated to quantify the nature of the drug interaction in each cell line model, wherein CI 1 indicates antagonism. For in vivo evaluation of combination therapy, we used the ER+ SKOV3-XDX model (an SKOV3 xenograft-derived tumorigenic variant developed in our laboratory). Tumor xenograft fragments were passaged by subcutaneous (s.c.) implantation into athymic nude mice. Following tumor development and randomized treatment group allocation, drug treatment was initiated with the following regimens: letrozole 10 μg s.c. for 5 consecutive days per week, abemaciclib 75mg/kg by daily oral gavage, or combination treatment with letrozole plus abemaciclib 50 mg/kg by daily oral gavage. Tumor volumes were measured every other day to evaluate the efficacy of treatment. Results: Intrinsic resistance to single agent letrozole was observed in all of the cell lines. Combination treatment with letrozole and abemaciclib was significantly more efficacious when compared with either drug alone, in both SKOV3 and Ishikawa. The CI values (0.5 and 0.7, respectively) demonstrated potent synergism in these ER+, RB-wildtype cell lines. Conversely, the RB-mutated cell line, A2780 was unresponsive to either drug alone or to combination therapy, and an antagonistic interaction (CI\u003e1) was observed. The efficacy of combination therapy using letrozole and abemaciclib was confirmed in vivo using the SKOV3-XDX ovarian cancer model. Conclusion: In laboratory models of ER+, RB-wildtype human ovarian and endometrial cancer, intrinsic endocrine therapy resistance is overcome by combination treatment with a CDK4/6 inhibitor plus AI. Potent synergism of abemaciclib and letrozole was observed in RB-wildtype endometrial and ovarian cancer cell lines, and combination treatment was efficacious and well-tolerated in vivo. Combination endocrine therapy merits further investigation in clinical trials including women with ER+, RB-wildtype gynecological cancers. Citation Format: Oloruntoba Ismail Osagie, Zhigui Li, Jing Ji, Gloria S. Huang. Combination of letrozole plus abemaciclib is synergistic and suppresses tumor growth in ovarian and endometrial cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4851.