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Updated: Jan 20, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
Shatha AbuHammad1, Carleen Cullinane1,2, Claire Martin1
1Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
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, 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.
Insights
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are vital for melanoma treatment sensitivity. Targeting PRMT5 alongside CDK4/6 inhibitors enhances efficacy and delays resistance by restoring p53 pathway activity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are established treatments for estrogen receptor-positive breast cancer.
- Melanoma exhibits high rates of CDK4 activation, making CDK4/6 inhibitors a potential therapeutic strategy.
- Acquired resistance to CDK4/6 inhibitors is a significant clinical challenge.
Purpose of the Study:
- To investigate the mechanism of acquired resistance to the CDK4/6 inhibitor palbociclib in melanoma.
- To identify key molecular pathways regulating CDK4/6 inhibitor sensitivity and resistance.
- To evaluate the therapeutic potential of combining CDK4/6 and PRMT5 inhibitors.
Main Methods:
- Analysis of melanoma cells with acquired resistance to palbociclib.
- Assessment of protein arginine methyltransferase 5 (PRMT5) activity and its role in CDK4/6 inhibition.
- Investigation of the MDM4-p53 pathway and its regulation by palbociclib.
- Preclinical evaluation of combination therapy with palbociclib and a PRMT5 inhibitor (GSK3326595).
Main Results:
- PRMT5 activity is essential for CDK4/6 inhibitor sensitivity in melanoma.
- Palbociclib indirectly suppresses PRMT5, altering MDM4 splicing, decreasing MDM4 protein, and activating p53.
- p53 activation leads to p21 induction, inhibiting CDK2 and overcoming resistance.
- Combination therapy with palbociclib and GSK3326595 enhanced efficacy and delayed resistance in preclinical models.
Conclusions:
- CDK4/6 inhibitors regulate the MDM4 oncogene and the tumor suppressor p53 through the PRMT5-MDM4 axis.
- Inhibition of the PRMT5-MDM4 axis is crucial for melanoma cell sensitivity to palbociclib.
- Combination therapy targeting both CDK4/6 and PRMT5 presents a promising strategy for melanoma and other cancers.
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