Abstract 1959: BLU-222, a potent and highly selective CDK2 inhibitor, demonstrates antitumor activity as monotherapy and as combination treatment in <i>CCNE1-</i>aberrant endometrial cancer models
Authors: Nealia House, Victoria Brown, Liang Yuan, Maxine Chen, Stephanie Lee, Rentian Wu, Lakshmi Muthuswamy, Scott Ribich, Philip Ramsden, Kerrie Faia
Journal: Cancer Research (2024)

Abstract Background: Many cyclin-dependent kinases (CDK) bind regulatory cyclins to control cell cycle progression. Aberrant CDK2 activation occurs in selected cancers (e.g., ovarian cancer, endometrial cancer) through CCNE1 amplification, leading to Rb phosphorylation, inactivation, and cell cycle checkpoint dysregulation. CCNE1 amplification and subsequent cyclin E overexpression are associated with chemotherapy resistance and shorter progression-free and overall survival. Therefore, novel therapies are needed to inhibit aberrant CDK2 activation and elicit positive clinical benefit in these patients. BLU-222 is a potent, highly selective, orally bioavailable, investigational CDK2 inhibitor with demonstrated activity in preclinical CCNE1-amplified ovarian cancer models. Here, we explored additional, specific biomarkers to predict BLU-222 sensitivity in ovarian and endometrial cancer as monotherapy or in novel combination treatment strategies. Methods: In vitro antiproliferative effect of BLU-222 was assessed by CyQuant in a panel of CCNE1-aberrant or CCNE1-normal ovarian and endometrial cell lines. Combination of BLU-222 and paclitaxel was evaluated by dosing matrix; synergy was calculated using SynergyFinder. In vivo antitumor activity of BLU-222 as a single agent or combined with paclitaxel was measured in CCNE1-aberrant endometrial cancer patient-derived xenograft (PDX) models (XenoSTART). Results: In ovarian and endometrial cell lines, CCNE1 amplification (copy number ≥ 6) predicted strong antiproliferative response to BLU-222. Using multivariate biomarker analysis, high p16 protein expression and wild-type Rb protein were identified as additional predictive markers for response to BLU-222 in CCNE1-aberrant cell lines. BLU-222 with paclitaxel was broadly active in endometrial cancer cell lines, with the strongest combination effect in cells with high CCNE1 expression, wild-type Rb protein, and low p16 protein expression. In vivo, BLU-222 elicited strong monotherapy antitumor response in CCNE1 copy number-aberrant endometrial cancer PDX models, and this effect was strengthened with the combination of paclitaxel. Conclusions: In preclinical models of CCNE1-aberrant endometrial cancer, BLU-222 demonstrated enhanced activity in combination with paclitaxel. Furthermore, Rb and p16 protein expression can be used in conjunction with CCNE1 copy number to predict response to both BLU-222 monotherapy and combination treatment. These data provide a rationale for using BLU-222 in combination with paclitaxel and demonstrate the potential benefit of using specific biomarkers to predict response. Citation Format: Nealia House, Victoria Brown, Liang Yuan, Maxine Chen, Stephanie Lee, Rentian Wu, Lakshmi Muthuswamy, Scott Ribich, Philip Ramsden, Kerrie Faia. BLU-222, a potent and highly selective CDK2 inhibitor, demonstrates antitumor activity as monotherapy and as combination treatment in CCNE1-aberrant endometrial cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1959.