Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines |
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| Authors: | Richard J Young Kelly Waldeck Claire Martin Jung H Foo Donald P Cameron Laura Kirby Hongdo Do Catherine Mitchell Carleen Cullinane Wendy Liu Stephen B Fox Ken Dutton‐Regester Nicholas K Hayward Nicholas Jene Alexander Dobrovic Richard B Pearson James G Christensen Sophia Randolph Grant A McArthur Karen E Sheppard |
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| Institution: | 1. Research Division, Peter MacCallum Cancer Centre, , East Melbourne, Vic., Australia;2. Pathology Department, Peter MacCallum Cancer Centre, , East Melbourne, Vic., Australia;3. Ludwig Institute for Cancer Research, Olivia Newton John Cancer and Wellness Centre, , Melbourne, Vic., Australia;4. Sir Peter MacCallum Department of Oncology, University of Melbourne, , Parkville, Vic., Australia;5. Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, , Brisbane, Qld, Australia;6. Department of Biochemistry and Molecular Biology, University of Melbourne, , Parkville, Vic., Australia;7. Pfizer Global Research and Development, La Jolla Laboratories, , San Diego, CA, USA |
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| Abstract: | We have investigated the potential for the p16‐cyclin D‐CDK4/6‐retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three‐quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma‐specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16INK4A) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance. |
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| Keywords: | melanoma
CDKN2A
CDK4 p16INK4A RB1 Cyclin D1 PD0332991 |
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