Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


New Drug May Overcome Cancer Treatment Resistance

An experimental drug could keep melanomas and breast cancer from resisting targeted therapies, according to findings reported at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. Called LEE011, the new drug inhibits proteins called cyclin-dependent kinases (CDKs), which make cells divide. The targeted CDKs are abnormally active in many cancers, including melanomas with BRAF mutations and breast cancers with PIK3CA mutations. The researchers found that LEE011 keeps cultured tumor cells from dividing and that combining the drug with targeted treatments prevents resistance in melanomas and breast cancer in mice. Now, these combination treatments are being tested in several phase I clinical trials on a variety of cancers in adults, as well as in children.


BRD4 Sustains Melanoma Proliferation and Represents a New Target for Epigenetic Therapy

“Metastatic melanoma remains a mostly incurable disease. Although newly approved targeted therapies are efficacious in a subset of patients, resistance and relapse rapidly ensue. Alternative therapeutic strategies to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell identity are emerging. Bromodomain and extraterminal domain (BET) proteins are epigenome readers known to exert key roles at the interface between chromatin remodeling and transcriptional regulation. Here, we report that BRD4, a BET family member, is significantly upregulated in primary and metastatic melanoma tissues compared with melanocytes and nevi. Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor–treated cells followed by Gene Ontology analysis showed a striking impact on transcriptional programs controlling cell growth, proliferation, cell-cycle regulation, and differentiation. In particular, we found that, rapidly after BET displacement, key cell-cycle genes (SKP2ERK1, and c-MYC) were downregulated concomitantly with the accumulation of cyclin-dependent kinase (CDK) inhibitors (p21 and p27), followed by cell-cycle arrest. Importantly, BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status, opening the possibility of using these small-molecule compounds to treat patients for whom no effective targeted therapy exists. Collectively, our study reveals a critical role for BRD4 in melanoma tumor maintenance and renders it a legitimate and novel target for epigenetic therapy directed against the core transcriptional program of melanoma.”