Abstract 4948: MDM2 antagonism overcomes resistance to CDK4/6 inhibition in melanoma

Metastatic melanoma is an aggressive disease characterized by resistance to conventional cancer treatments such as radiation and chemotherapy. While immune checkpoint blockade and BRAF inhibitor therapies are effective in many melanoma cases, a significant proportion of patients are resistant to these standard of care treatments and thus require new therapeutic approaches. We hypothesized that targeting CDK4/6 may offer hope to melanoma patients refractory to immunotherapy and BRAF inhibition, based on CDK4 being a key oncogene activated by mutations or deletions of CDKN2A gene, which are very common in melanoma (>50% of cases). However, in vivo studies using our extensive collection of melanoma patient-derived xenografts (PDX) showed that the majority of melanoma tumors are intrinsically resistant to CDK4/6 inhibition. We identified the mechanism of this resistance which was driven by cooperative activities of other CDKs expressed by tumor cells that compensated for the loss of CDK4/6 function to allow cell cycle progression through G1 and S phases. In order to overcome compensatory activation of other CDKs, we used small molecule antagonists of MDM2-p53 interaction, that stabilize p53 protein, which, in turn, upregulates an endogenous pan-CDK inhibitor, p21. Notably, combined MDM2 and CDK4/6 antagonism resulted in greater inhibition of tumor growth than either inhibitor individually. This synergistic effect was observed in multiple melanoma PDX models and in immunocompetent mice bearing mouse melanoma tumors. In summary, our preclinical data suggest that combining CDK4/6 inhibitors with MDM2 antagonists is a promising strategy for the treatment of metastatic melanoma, which should be further tested by a clinical study. Citation Format: Anna E. Vilgelm, Nabil Saleh, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chian Chen, Gregory D. Ayers, Rondi M. Kauffman, Mark C. Kelley, Douglas B. Johnson, Ann Richmond. MDM2 antagonism overcomes resistance to CDK4/6 inhibition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4948.