Journal article
Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
S AbuHammad, C Cullinane, C Martin, Z Bacolas, T Ward, H Chen, A Slater, K Ardley, L Kirby, KT Chan, N Brajanovski, LK Smith, AD Rao, EJ Lelliott, M Kleinschmidt, IA Vergara, AT Papenfuss, P Lau, P Ghosh, S Haupt Show all
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2019
Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, lea..
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Grants
Awarded by National Cancer Institute
Funding Acknowledgements
We thank the staff of the following Peter MacCallum Cancer Centre core facilities: the Victorian Centre for Functional Genomics; the Molecular Genomics facility; and the Flow Cytometry facility. We thank the MD Anderson RPPA core facility for performing the RPPA screening. We thank Rachael Walker and Susan Jackson for assisting in the in vivo study. We thank Dr. Maria Doyle (Research Computing) for bioinformatic assistance. We thank Associate Professor Marco Herold (Walter and Eliza Hall Institute) for providing the MDM4 silencing vector; Dr. Gareth Gregory and Prof. Ricky Johnston for providing CDK2 shRNA constructs; and Prof. Shereen Loi, Dr. Joyce Teo, Prof. Wayne Phillips, and Dr. Nicholas Clemmens for providing breast, pancreatic, and esophageal cancer cell lines. We thank Dr. Twishi Gulati for editorial assistance. We acknowledge Cancer Therapeutics CRC for partly funding the in vivo studies. This work was supported by the Peter MacCallum Cancer Foundation; and by Cancer Council Victoria Grant 1108149 and National Health and Medical Research Council of Australia Grant 1042986 (to K. E. S. and G. A. M.). S. A. was supported by doctoral scholarships from the University of Melbourne and Cancer Therapeutics CRC.