Abstract 3096: CDK4/6 as a therapeutic target in malignant melanoma

Abstract

Abstract Melanoma is the most deadly form of skin cancer and FDA-approved therapies such as vemurafenib and ipilimumab are associated with short-term responses and/or severe toxicities for patients. Recent favorable clinical data with cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib (PD’991) in ER+ breast cancer has rekindled an interest in targeting cell cycle progression to stop aberrant cell growth. Thus, we set out to analyze the potential use of CDK4/6 inhibitors in melanoma. Due to the inability of CDK4/6 inhibitors to induce apoptosis as a single agent, we explored viable combinatorial strategies that will trigger both pro-senescent and pro-apoptotic pathways that may lead to an effective treatment modality for melanoma patients. Here, we demonstrate the benefit of combining a MEK inhibitor, trametinib (GSK’212) with PD’991 both in vitro and in vivo. We did not observe any enhanced effects of combining both GSK’212 and PD’991 in cells that are wild-type for BRAF and NRAS or an RB1-null BRAF mutant line. However, B-RAF and N-RAS mutant cells exhibited an enhanced response to the combinatorial agents as compared to single agents. Furthermore, we observed a dramatic increase in apoptosis in cell lines that are sensitive to combined GSK’212 and PD’991 treatment. Expression of Inhibitor-of-Apoptosis (IAP) protein, survivin, was associated with response. Finally, because it is important to understand how resistance develops, we have validated a novel E2F reporter system in vivo to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and possible re-activation of the pathway during acquired drug resistance. Citation Format: Jessica L. Teh, Andrew Aplin. CDK4/6 as a therapeutic target in malignant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3096. doi:10.1158/1538-7445.AM2015-3096