Journal Article

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

Falk, Hendrik, Ardley, Kerry, Kleinschmidt, Margarete, Papenfuss, Anthony T., Haupt, Sue, Haupt, Ygal, Chan, Keefe T., Stupple, Paul, Ghosh, Prerana, Lau, Peter, Bacolas, Zoe, Poortinga, Gretchen, Rao, Aparna D., Smith, Lorey K., AbuHammad, Shatha, Lelliott, Emily J., Curtis, David J., Chen, Huiqin, Pearson, Richard B., Vergara, Ismael A., Sanij, Elaine, Cullinane, Carleen, Kirby, Laura, Davies, Michael A., Brajanovski, Natalie, Ward, Teresa, Devlin, Mark, Martin, Claire, Slater, Alison, McArthur, Grant A., Street, Ian, Sheppard, Karen E.

2019

Overview

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, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

• Publisher: National Academy of Sciences
• Subject: Arginine / Biological Sciences / Breast cancer / Cell activation / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - genetics / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - antagonists & inhibitors / Cyclin-Dependent Kinase 4 - genetics / Cyclin-Dependent Kinase 4 - metabolism / Cyclin-Dependent Kinase 6 - antagonists & inhibitors / Cyclin-Dependent Kinase 6 - genetics / Cyclin-Dependent Kinase 6 - metabolism / Cyclin-dependent kinases / Drug Resistance, Neoplasm / Esophageal carcinoma / Esophagus / Estrogens / GTP-binding protein / HEK293 Cells / Humans / Inhibitors / Kinases / MCF-7 Cells / Medical Sciences / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - metabolism / Melanoma - pathology / Menopause / mRNA / p53 Protein / Pancreas / Pancreatic carcinoma / Piperazines - pharmacology / PNAS Plus / Protein arginine methyltransferase / Protein Kinase Inhibitors - pharmacology / Protein-Arginine N-Methyltransferases - antagonists & inhibitors / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - metabolism / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Pyridines - pharmacology / Sensitivity / Splicing / Tumor suppressor genes / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors