Poster Presentation 29th Lorne Cancer Conference 2017

Targeting PRMT5 in CDK2 driven resistance to CDK4 inhibitors in melanoma. (#104)

Shatha AbuHammad 1 , Mark Devlin 1 , Grant McArthur 1 , Karen Sheppard 1
  1. Research Department , Peter MacCallum Cancer Centre, Melbourne , VIC, Australia

Targeting the cell cycle is a new appealing approach for treating melanoma, alongside the recent development of MAPK/ERK pathway inhibitors and immunotherapy, which has revolutionized the treatment of metastatic melanoma. Despite these remarkable improvements, the efficacy of targeted therapy is limited by the development of drug resistance. The aims of this study is to identified mechanisms that lead to the development of resistance to CDK4 inhibitors in melanoma and provide effective combinational treatment to overcome it.

In a panel of CDK4/6 inhibitor (palbociclib) resistant melanoma cell lines, cellular mechanistic studies revealed that resistance to palbociclib is due to activation of the CDK2 pathway, which occurs due to loss of p21, an inhibitor of CDK2, or an increase in cyclin E1 levels. To identify drugs that could circumvent palbociclib resistance we performed a high throughput drug screen, the results indicated that several palbociclib-resistant cell lines were more sensitive to PRMT5 inhibitors compared to the parental cell lines. Proliferation assays also showed that combining palbociclib with the PRMT5 inhibitor EPZ-208 overcomes the resistance to palbociclib and inhibits the growth of the cells. Our data indicate that PRMT5 inhibition decreases CDK2 activity via modulating p21 and Cyclin E1, we are currently further investigating the mechanisms underlying this response.

In summary, the outcome of this research will allow the development of novel combination strategies to prevent or overcome the emergence of resistance to CDK4 inhibitors, and to identify predictive biomarkers of response, which will improve the personalisation of treatment regimens.