Abstract 4850: Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib

Abstract

Background: Prostate cancer (PCa) is a leading cause of cancer death in men and represents a substantial public health burden [1]. Most PCa are primarily dependent on androgen receptor (AR) activity and castration is an effective approach to treat PCa patients. Despite the recent significant treatment advances, PCa inevitably becomes androgen-independent and progresses to the castration-resistant disease state (CRPC), the deadliest form of the disease [2]. Progression of the disease to castration-resistance is often mediated by a reactivation of AR signaling pathway [3]. Upon androgen stimulation, expression of D-type cyclin is up-regulated which results in an increased cyclin-dependent kinase 4 and 6 (CDK4/6) activity and stimulation of the cell cycle. [4]; Thus, inhibition of CDK4/6 may represent an effective strategy to delay or overcome primary androgen resistance. Abemacicilb is a CDK4 and CDK6 inhibitor with a clinical safety profile allowing continuous dosing to achieve sustained target inhibition [5]. Abemaciclib is FDA-approved for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer [6,7]. Methods: The anti-proliferative activity of the abemaciclib was evaluated using iodide staining in a panel of 15 PCa cell lines. In order to get new insights on abemaciclib effects, deeper in vitro analysis was carried out in LNCaP, PC-3 and 22RV1, as ADT responding and resistant PCa cell models, respectively. Cell cycle analysis was done by FACS and High Content Imaging; cellular signaling was assessed by Western blotting. Apoptosis was measured by detection of caspase 3 and Tunnel assay. 22RV1 xenograft mouse model was used to evaluate abemaciclib efficacy in vivo. Results: Anti-proliferative activity of abemaciclib was observed across a panel of PCa cell lines, mainly in hormone receptor positive (AR+) cell lines. Overall, abemaciclib efficiently inhibited CDK4 and CDK6 which prevented the phosphorylation of Rb with the consequent effect in cell cycle and induced a G1 cell cycle arrest. Prolonged treatment promoted a marked senescence phenotype indicated by an increased b-galactosidase staining and morphological changes to result ultimately in apoptosis. In 22RV1 xenograft models, abemaciclib significantly reduced tumor growth. Taken together these data provide insights on sensitivity of PCa models to abemaciclib and its mode of action, demonstrating the potential of this drug for the treatment of prostate cancer patients. Conclusions: Abemaciclib inhibits proliferation of AR positive prostate cancer cell lines by inducing cell cycle arrest mediated by inhibition of Rb phosphorylation. Abemaciclib is a CDK4/6 inhibitor with potential to treat prostate cancer by blocking cell proliferation leading to induction of senescence and apoptosis. Citation Format: Raquel Torres-Guzmán, Carmen Baquero, Maria Patricia Ganado, Carlos Marugán, Huimin Bian, Yi Zeng, Ramón Rama, Jian Du, Maria José Lallena. Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib [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 4850.

Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?

“…Preclinical data have demonstrated the ability from abemaciclib to enhance effective senescence in prostate cancer cells expressing AR. These data have also been obtained with AR+ Prostate 22RV1 Xenograft models showing a tumor reduction with abemaciclib treatment [ 169 ]. Therefore, clinical trials have been designed and are currently ongoing with CDK4/6 inhibitors in monotherapy [ 170 , 171 ], but also in combination [ 172 , 173 , 174 , 175 , 176 ] in prostate cancer.…”

Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib

“…Elevated levels of androgen receptor (AR) and PIK3CA – activating mutations were also associated with sensitivity, although these markers were detected in cell lines of the luminal BC subtype and therefore may not be independent indicators of response. 50 Though, Torres-Guzmán et al 51 did also observe antiproliferative activity across a panel of AR-positive prostate cancer cell lines, however while this finding is intriguing, the study was not powered to support the utility of AR as a molecular determinant of response to abemaciclib. Potential biomarkers of sensitivity were also identified in BC xenograft models.…”

A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration–Resistant Prostate Cancer: Results from CYCLONE 1

“… 9 ). Furthermore, pharmacological inhibition of CDK4/6 led to robust cell-cycle arrest and tumor growth inhibition in prostate cancer models ( 10 ).…”