Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

• DOI: 10.1073/pnas.1901323116
• Publication Date: 2019-08-22T23:25:20Z
• Authors: Shatha AbuHammad; Carleen Cullinane; Claire Martin; Zoe Bacolas; Teresa Ward; Huiqin Chen; Alison Slater; Kerry Ardley; Laura Kirby; Keefe T. Chan; Natalie Brajanovski; Lorey K. Smith; Aparna D. Rao; Emily J. Lelliott; Margarete Kleinsc...; Ismael A. Vergara; Anthony T. Papenfuss; Peter Lau; Prerana Ghosh; Sue Haupt; Ygal Haupt; Elaine Sanij; Gretchen Poortinga; Richard B. Pearson; Hendrik Falk; David J. Curtis; Paul Stupple; Mark Devlin; Ian Street; Michael A. Davies; Grant A. McArthur; Karen E. Sheppard
• Keywords: Palbociclib; Cyclin-dependent kinase 4; Retinoblastoma protein

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and currently clinical development melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib demonstrate activity PRMT5, protein arginine methyltransferase indirect target CDK4, is essential for sensitivity. By indirectly suppressing PRMT5 activity, alters pre-mRNA splicing MDM4, negative regulator p53, leading decreased MDM4 expression subsequent p53 In turn, induces p21, inhibition CDK2, main substituting key driver palbociclib. Loss ability regulate PRMT5-MDM4 axis leads resistance. Importantly, combining GSK3326595 enhances efficacy treating naive resistant models also delays emergence Our studies have uncovered mechanism action regulating oncogene suppressor, p53. Furthermore, we robust cell sensitivity provide preclinical evidence coinhibition effective well-tolerated therapeutic strategy. Overall, our data strong rationale further investigation novel combinations inhibitors, not only but other types, including breast, pancreatic, esophageal carcinoma.