E-Poster Presentation 33rd Lorne Cancer Conference 2021

Inhibiting PRMT5: A novel therapeutic strategy for MAPK inhibitor-resistant melanoma  (#175)

Lydia Lim 1 , Jonathan Naddaf 1 , Shatha AbuHammad 1 , Alison Slater 1 , Laura Kirby 1 , Lorey Smith 1 , Emily Lelliott 1 , Riyaben Patel 1 2 , Grant McArthur 1 3 4 , Karen Sheppard 1 3 5
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne , VIC, Australia
  2. The University of Melbourne , Melbourne , VIC, Australia
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne , VIC, Australia
  4. Department of Medicine, St. Vincent’s Hospital, The University of Melbourne , Melbourne , VIC, Australia
  5. Department of Biochemistry and Pharmacology, The University of Melbourne , Melbourne , VIC, Australia

In BRAF-mutant melanoma, the current standard of care involves a combination therapy of BRAF and MEK inhibitors (BRAFi/MEKi) which target components of the MAPK/ERK signalling pathway. However, success of targeted therapies in treating metastatic melanoma is hampered by both acquired and inherent drug resistance, mainly contributed by overactivation of the MAPK/ERK pathway. Recent pre-clinical studies from our lab demonstrated that co-inhibiting CDK4/6 and PRMT5, both downstream of the MAPK/ERK pathway, was an effective therapeutic strategy in BRAF-mutant melanoma. Hence, we hypothesised that BRAFi-resistant melanoma cells would also respond to the dual inhibition of CDK4/6 and PRMT5, considering CDK4/6 and PRMT5 lie downstream of the activating events that lead to BRAFi/MEKi-resistance. Dose-response assays, revealed that melanoma cells that have increased resistance to BRAFi remain sensitive to CDK4/6 inhibitors (CDK4/6i) and PRMT5 inhibitors (PRMT5i). More importantly, co-inhibiting CDK4/6 and PRMT5 suppressed cell proliferation in resistant cells. shRNA knockdown of p53 decreased sensitivity to combination  CDK4/6 and PRMT5 inhibition; suggesting p53 plays a role in the robust response in p53WT cells to this novel therapy. Surprisingly, the combination was also very effective in p53 mutant cells. Overall, evidence from our studies support the functional cooperativity of CDK4/6i and PRMT5i as a combination therapy, which can exert effects in a p53-dependent or independent manner, thus serving as a potential treatment strategy for BRAF-mutant melanoma patients that either have primary resistance or acquired resistance to BRAFi/MEKi.

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