Role of dual specificity phosphatases (DUSPs) in melanoma cellular plasticity and drug resistance

Abstract

Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often associated with drug resistance. The mechanisms that control melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that emergence of MAPK inhibitor (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated melanoma cells. Here, we show that knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decrease the survival of MAPKi-resistant cells and sensitizes them to BRAFi and MEKi. Pharmacological inhibition of DUSP1/6 upregulated nestin, a neural crest stem cell marker, in both MAPKi-sensitive cells and cells with acquired MAPKi-resistance. In contrast, treatment with BCI resulted in upregulation of MAP2, a neuronal differentiation marker, only in MAPKi-sensitive cells but caused downregulation of both MAP2 and GFAP, a glial marker, in all MAPKi-resistant cell lines. These data suggest that DUSP proteins are involved in the regulation of cellular plasticity cells and melanoma drug resistance and are potential targets for treatment of MAPKi-resistant melanoma.

Spatiotemporal profiling defines persistence and resistance dynamics during targeted treatment of melanoma

“…[20][21][22] DUSP proteins have also been noted to play a role in cellular plasticity and melanoma drug resistance. 23 We find significant upregulation of several DUSP family genes (DUSP 1, 5, 7, 8, 10) upon initiation of treatment in the sensitive but not the resistant lineages, whereas DUSP4 expression is strongly suppressed in the resistant but not the sensitive lineages (Figure 6b/c, Supplementary Figure 7). These DUSP effects are not seen in comparisons of the untreated-early (T0) vs. untreated-late (TC) samples.…”

“…Specifically, the dual specific phosphatase (DUSP) family represents a promising potential target for intervention. 23,23…”

BCI, an inhibitor of the DUSP1 and DUSP6 dual specificity phosphatases, enhances P2X7 receptor expression in neuroblastoma cells

“…BCI is a small-molecule that acts as a dual-inhibitor of DUSP1 and DUSP6, exerting anti-tumorigenic activity in a wide range of cancer models ( Figure 1A ) ( Kaltenmeier et al, 2017 ; Wu et al, 2018 ; James et al, 2019 ; Ramkissoon et al, 2019 ; Duan et al, 2021 ; Nair et al, 2021 ; Singh et al, 2022 ). In SH-SY5Y human neuroblastoma cells, BCI elicits a dose-dependent decrease in ERK activity and reduces the viability of these cells ( Mendell and MacLusky, 2019 ).…”

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

“…Singh et al. [21] focused on MAPK pathway inhibitors against different DUSPs in relation to their contribution to plasticity and resistance and found that the downregulation of DUSP1 specifically leads to plasticity in melanoma cells. DUSPs are negative regulators of the MAPK pathway and act in tandem to maintain cell proliferation and survival.…”

“…Loss of Dual specificity phosphate-4 (DUSP4), a negative regulator of the MAP kinase superfamily, leads to the development of a CSC-like phenotype in basal breast cancer, which confers plasticity to cells [20]. Singh et al [21] focused on MAPK pathway inhibitors against different DUSPs in relation to their contribution to plasticity and resistance and found that the downregulation of DUSP1 specifically leads to plasticity in melanoma cells. DUSPs are negative regulators of the MAPK pathway and act in tandem to maintain cell proliferation and survival.…”