Discoidin domain receptors: A promising target in melanoma

Abstract

The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1‐IN‐1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.

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

“…Our functional in vitro studies also showed a key role for DDR1 in melanoma cell proliferation, migration, invasion, and survival (43). Importantly, a pan-DDR inhibitor, DDR1-IN-1 (46), with higher selectivity toward DDR1 than to DDR2, decreased tumor growth in BRAF-mutated human melanoma xenograft models (43). Because melanoma and stromal cells also express DDR2, these preclinical studies with DDR1-IN-1 suggest that DDR1, and possibly DDR2, constitutes a potentially new target in melanoma (43).…”

“…Analyses of skin samples harboring melanoma showed a strong expression of DDR1 in the melanoma cells, which was positively correlated with invasive depth and patient survival. Our functional in vitro studies also showed a key role for DDR1 in melanoma cell proliferation, migration, invasion, and survival (43). Importantly, a pan-DDR inhibitor, DDR1-IN-1 (46), with higher selectivity toward DDR1 than to DDR2, decreased tumor growth in BRAF-mutated human melanoma xenograft models (43).…”

“…Regardless, CCN3-mediated DDR1 upregulation was proposed to play a major role in the adhesion of melanocytes to the BM and in the maintenance of skin homeostasis (45). While these in vitro studies suggested a role for DDR1 in melanocytes in normal skin, our recent immunohistochemical analyses in human skin sections demonstrated that DDR1 immunoreactivity was only detected in normal keratinocytes, albeit at relatively low levels of expression (43). Moreover, we found no detectable DDR1 expression in benign naevi in all cell types.…”

“…Importantly, a pan-DDR inhibitor, DDR1-IN-1 (46), with higher selectivity toward DDR1 than to DDR2, decreased tumor growth in BRAF-mutated human melanoma xenograft models (43). Because melanoma and stromal cells also express DDR2, these preclinical studies with DDR1-IN-1 suggest that DDR1, and possibly DDR2, constitutes a potentially new target in melanoma (43). Based on these results, we posit that DDRs are promising therapeutic targets in BRAF-mutated melanomas.…”

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

“…). It was demonstrated that DDR1 expression in melanoma lesions correlates with poor prognosis(Reger de Moura et al 2019). Furthermore, different studies demonstrated a role of DDR1 in resistance in breast cancer, ovarian cancer and glioblastoma cells(Aljohani et al 2015;Das et al 2006a; Deng et al.…”