Discoidin Domain Receptors in Melanoma: Potential Therapeutic Targets to Overcome MAPK Inhibitor Resistance

Abstract

Melanoma is a highly malignant skin cancer with high propensity to metastasize and develop drug resistance, making it a difficult cancer to treat. Current therapies targeting BRAF (V600) mutations are initially effective, but eventually tumors overcome drug sensitivity and reoccur. This process is accomplished in part by reactivating alternate signaling networks that reinstate melanoma proliferative and survival capacity, mostly through reprogramming of receptor tyrosine kinase (RTK) signaling. Evidence indicates that the discoidin domain receptors (DDRs), a set of RTKs that signal in response to collagen, are part of the kinome network that confer drug resistance. We previously reported that DDR1 is expressed in melanomas, where it can promote tumor malignancy in mouse models of melanoma, and thus, DDR1 could be a promising target to overcome drug resistance. In this review, we summarize the current knowledge on DDRs in melanoma and their implication for therapy, with emphasis in resistance to MAPK inhibitors.

Keywords: DDR1; MAPK inhibitors; drug resistance; melanoma; therapeutic target.

FIGURE 1

DDR1 expression in melanoma samples as a function of expression and mutational status of BRAF (A,B) or NRAS (C,D). Transcript abundances were quantified using RSEM (50) on a log2 scale. The red dashed lines indicate the typical cutoff for expressed genes [RSEM = log2(100)]: samples below the red lines are assumed to have no or very low expression. Classification of melanoma subtypes into mutant BRAF, mutant RAS, mutant NF1, and triple-WT (wild-type) was obtained from TCGA (51). (A) DDR1 expression for BRAF wild-type (left, blue) and mutated cases (right, red). (B) DDR1 versus BRAF expression for WT (blue) and BRAF-mutated cases (red). 80% of the samples show co-expression of DDR1 and BRAF (upper-right quadrant). (C) DDR1 expression for NRAS wild-type (left, blue) and mutated cases (right, red). (D) DDR1 versus NRAS expression for wild-type (blue) and cases with NRAS mutations (red). (E) DDR1 expression in melanoma molecular subtypes (BRAF, NRAS, NF1 mutated, and triple WT). There is no significant difference in the median expression of DDR1 (p-value > 0.05, Wilcoxon rank-sum test), but we note some outliers with low DDR1 expression in the NF1 mutant, RAS mutant, and triple WT cases (three left-most plots), while no outliers with low expression are observed for the BRAF mutant subtype. N, normal; T, tumor.