Analysis of the genome to personalize therapy for melanoma

Abstract

The treatment of cancer is being revolutionized by an improved understanding of the genetic events that occur in tumors. Advances in the understanding of the prevalence and patterns of mutations in melanoma have recently led to impressive results in trials of personalized, targeted therapies for this disease. In this review, we will discuss the molecular targets that have been validated clinically, additional genetic events that are candidates for future trials, and the challenges that remain to improve outcomes further in this aggressive disease.

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1

Kinase signaling pathways in melanoma. The majority of melanomas harbor somatic mutations in the RAS-RAF-MEK-MAPK or PI3K-AKT pathways. Activating mutations are indicated by rippled red and blue circles, with intensity denoting relative prevalence. Loss of function mutations are highlighted in red. RPTK, receptor protein tyrosine kinase (that is, c-KIT, ERBB4).

Figure 2

Genetic and functional analysis of ERBB4 mutations. Flowchart representing the experimental design used to evaluate the presence of somatic mutations in the tyrosine kinome in melanoma and its functional follow-up. Once ERBB4 was found to be the most highly mutated tyrosine kinase, seven of its mutations were shown to (from left to right) increase its kinase activity, induce cell transformation and provide an essential cell survival signal as seen in small hairpin RNA (shRNA) knockdown and small molecule inhibition assays. WT, wild type. Figure adapted from Prickett et al., 2009.