BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
The retinoblastoma (RB) and TP53 tumor suppressor pathways are dysregulated in many sporadic and familial melanomas, and all known inherited high-risk melanoma susceptibility loci are genes in the RB pathway. However, loss or lesions of RB and TP53 occur much less frequently in sporadic melanomas than in most other solid tumors. Instead, genetic alterations in CDKN2A can eliminate upstream signaling in these pathways in melanoma. The CDKN2A locus at chromosome 9p21 encodes four exons, and alternative splicing yields two distinct tumor suppressors that share a common second exon: p16INK4a and p14ARF . Mutations in p16INK4A functionally inactivate the RB pathway while mutations in p14ARF functionally inactivate the p53 pathway. The most common CDKN2A lesions in melanoma are point mutations, which are found as germline lesions in 25–40% of familial melanomas and as sporadic alterations in 10% of non-familial melanomas . CDKN2A point mutations are also associated with dyplastic nevi. As with PTEN loss, CDKN2A mutation tends to coincide with BRAF mutation .
The RB pathway regulates the G1/S cell cycle checkpoint. During normal cell cycle progression, the RB tumor suppressor is phosphorylated by mammalian G1 cyclin-CDK complexes. Hyperphosphorylation of RB triggers release of E2F family members, transcription factors that activate expression of genes important for entry into S phase and DNA synthesis. p16INK4a binds and inhibits cyclin-dependent kinases 4 and 6 (CDK4/6) from inappropriately phosphorylating the RB protein . Thus, loss of p16INK4a facilitates RB phosphorylation and subsequent re-entry into the cell cycle. Point mutations or transcriptional silencing are responsible for loss of p16INK4a expression in 30–70% of melanomas, leading to increased cellular proliferation and escape from oncogene-induced senescence.
Activating mutations in CDK4 are found in a small number of melanomas. CDK4 germline mutations always occur at a conserved arginine residue, R24, that is necessary for regulatory inhibition of CDK4 by p16INK4a [8, 69]. 5% of melanomas contain somatic CDK4 point mutation or amplification . p16INK4a and CDK4 mutations are mutually exclusive [29, 71, 72].
While TP53 mutations are found in 5% of melanomas , the p53 apoptotic pathway is more often deficient due to loss of p14ARF function in melanomas . p14ARF binds and inhibits the mouse double minute 2 homolog (MDM2). MDM2 encodes an E3 ubiquitin ligase that inhibits p53 transcriptional activity and targets p53 for proteasomal degradation. Inactivating p14ARF mutations permit the p53antagonizing activity of MDM2 and subsequent genomic instability [75–77]. In rare cases, amplification of MDM2 without alterations in CDKN2A sequence or expression has been observed in melanoma .
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