This review highlights recent clinical developments in the therapeutic targeting of cell cycle control in melanoma with cyclin-dependent kinase inhibitors, checkpoint kinases, MDM2, MDM4 and p53 inhibitors.
The high prevalence of activating genetic aberrations along the p16INK4A:cyclinD-CDK4/6:RB pathway in melanoma and increasing evidence that alterations in this pathway are linked to melanomagenesis, make targeting the p16INK4A:cyclinD-CDK4/6:RB pathway in melanoma logical and highly attractive. The presence of elevated CDK4 activity appears to correlate with greater CDK4/6 inhibitor therapeutic activity, whereas the loss of RB1 has been linked to CDK inhibitor resistance. Other novel compounds targeting cell cycle control via reactivating wild-type p53 and checkpoint kinases are also currently under investigation in melanoma.
Cell cycle control is a promising target in the management of melanoma with early data reporting therapeutic benefit with cyclin-dependent kinase inhibitors, MDM2, and p53 reactivation compounds. Many of these drugs have entered phase I and II clinical trial development. Preliminary data from these studies are discussed in this review along with future treatment strategies for maximizing treatment outcomes in advanced melanoma.
aDepartment of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne
bDepartment of Pathology, University of Melbourne, Parkville
cDepartment of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy
dMolecular Oncology Laboratory, Oncogenic Signalling and Growth Control Program
eTranslational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Correspondence to Professor Grant McArthur, MBBS (Hons), PhD, FRACP, Assistant Executive Director of Cancer Research NHMRC Practitioner Fellow, Consultant Medical Oncologist, Co-Head Cancer Therapeutics Program, Director Melanoma and Skin Service, Lorenzo Galli Chair in Melanoma and Skin Cancers University of Melbourne, Research Division, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne VIC 8006, Australia. Tel: +61 3 9656 1954; fax: +61 3 9656 3717; e-mail: email@example.com
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