Melanoma is considered the most aggressive type of skin cancer with a rapidly increasing incidence worldwide 1, 2. While the genetic bases of melanoma are complex, the recent advances in molecular genetics has led to a greater understanding of the genetic and molecular heterogeneity of melanoma 3. A major breakthrough occurred when it was shown that germline mutations in the CDKN2A locus and CDK4 are very high in familial melanoma 2 and activation of CDK4 occurs in the majority of cutaneous melanomas 4. CDK4 is the key regulator of G1/ S progression during cell cycle, it forms a complex with cyclin D, to phosphorylate and inhibit retinoblastoma protein, consequently drive cell cycle progression. This process is inhibited by p16, which is encoded by the CDKN2A locus 4. Disrupting this axis is a valid approach to control the unrestrained growth of cancer cells, therefore provides an important therapeutic target to treat melanoma. CDK4 inhibitors have shown in vitro activity against a broad range of cancers, and antitumor activity in patients with breast cancer, lymphoma, sarcoma, and other tumours 5; moreover we have previously demonstrated the efficacy of CDK4 inhibition in a panel of melanoma cell lines 6.
Despite the great potential CDK4 inhibitors hold, our preliminary data suggests that upon continuous exposure to the drug, resistance to these inhibitors will eventually develop. Furthermore, some melanoma cell lines have shown to be inherently less sensitive to the drug.
This project focuses on developing rational combinations of CDK4 inhibitors with numerous molecularly targeted therapies to enhance CDK4 inhibitors efficacy and overcome resistance. A panel of melanoma cell lines was screened against a group of compounds that target various cellular processes in order to explore the feasibility of combining these compounds with the CDK4 inhibitor Palbociclib.