Abstract B11: Manipulating senescence to combat melanoma initiation and progression

Abstract

Abstract Senescence has been identified as a tumor suppression mechanism in many premalignant tissues. The most widely studied example is the melanocytic nevus that guards against the onset of melanoma. Senescence therefore acts as a barrier to malignancies and reinforcing this growth-arrested state can be a valuable way to combat tumorigenesis. Accordingly, therapy induced senescence (TIS) has been shown to be a promising approach for treatment of cancer. Here we further study how specific factors govern TIS. Numerous clinical trials are currently ongoing that inhibit MDM2 or CDK4/6, which regulate the tumor suppressors p53 and RB/p16, respectively. As these tumor suppressors are the master regulators of senescence and senescence is an important mechanism in melanoma initiation, we analyzed the effect of their inhibition in primary melanocytes and transformed melanoma cell lines. As anticipated, we show that upon administration of the MDM2 and CDK4/6 inhibitors (-)-Nutlin-3a (1uM) and PD2991 (8uM, respectively), primary human melanocytes and human melanoma cell lines stop proliferating. While MDM2 and CDK4/6 inhibitors have been shown to induce senescence, we were surprised to find that induction of senescence was not conserved among all cell types studied. Analysis of the cell cycle arrest showed that human melanocytes do not display senescence associated beta-galactosidase activity while melanoma cell lines do stain positive for this marker of senescence. Furthermore, members of the senescence associated secretory phenotype (SASP) are not increased upon MDM2 and CDK4/6 inhibition in primary melanocytes, whereas the same treatment in melanoma cells causes SASP up-regulation in a similar fashion to that triggered by oncogene induced senescence (OIS). The induction of the SASP members was particularly evident upon combined treatment with MDM2 and CDK4/6 inhibitors. These results suggest that TIS may be influenced by the expression of the SASP. We have previously showed that many members of the SASP whose expression increases with senescence also expressed in metastatic disease. By further evaluating SASP following OIS vs TIS, we may better understand the mechanisms behind existing senescence inducing therapies and define additional routes for pro-senescence cancer therapy. Senescence is a highly complex process that is able to control multiple cell fates, often due in part to the SASP. Consequently, by manipulating the SASP we may be able to regulate melanoma initiation and progression. Citation Format: Jeff S. Pawlikowski, Malorie Holmes, Ann Richmond. Manipulating senescence to combat melanoma initiation and progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B11.