Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway

Abstract

Although the utilization of selective BRAFV600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAFV600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAFV600E- bearing melanoma cells. Dual targeting of CDC7 and BRAFV600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase

“…Selective inhibition of CDC7 suppresses proliferation of transformed cells through induction of S-phase delay and replication stress ( Cheng et al., 2018 , Im and Lee, 2008 , Ito et al., 2012 , Iwai et al., 2019 , Montagnoli et al., 2004 ). Furthermore, CDC7 antagonists showed promise in combination with other cell-cycle inhibitors and anti-cancer therapeutics ( Cao and Lu, 2019 , Gad et al., 2019 , O' Reilly et al., 2018 ). Selective inhibitors of CDC7 are being developed and trialed as anti-cancer therapeutics, with a number of candidate drugs undergoing clinical trials ( Cheng et al., 2018 , Gallagher et al., 2019 , Huggett et al., 2016 , Iwai et al., 2019 , Koltun et al., 2012 , Kurasawa et al., 2020 , Sawa and Masai, 2009 , Swords et al., 2010 , Vanotti et al., 2008 ).…”

Molecular Signature of Small Cell Lung Cancer after Treatment Failure: The MCM Complex as Therapeutic Target

“…Our expression signature revealed that cell division cycle 7 ( CDC7 ) was overexpressed in SCLC tissues after treatment failure. CDC7 is a crucial kinase required for initiating the replication machinery [ 37 ], and its overexpression has been reported in various cancers [ 37 , 38 , 39 ]. Importantly, CDC7 phosphorylates the MCM complex to activate its helicase function [ 39 , 40 , 41 ].…”

“…CDC7 is a crucial kinase required for initiating the replication machinery [ 37 ], and its overexpression has been reported in various cancers [ 37 , 38 , 39 ]. Importantly, CDC7 phosphorylates the MCM complex to activate its helicase function [ 39 , 40 , 41 ]. In melanoma cells, a sustained CDC7 expression and associated MCM2–7 activation were observed in vemurafenib-resistant cells, and the CDC7 inhibitor TAK-931 was suggested as a therapeutic option for vemurafenib-resistant melanoma cells [ 39 ].…”

“…Importantly, CDC7 phosphorylates the MCM complex to activate its helicase function [ 39 , 40 , 41 ]. In melanoma cells, a sustained CDC7 expression and associated MCM2–7 activation were observed in vemurafenib-resistant cells, and the CDC7 inhibitor TAK-931 was suggested as a therapeutic option for vemurafenib-resistant melanoma cells [ 39 ]. CDC7 overexpression and constitutive MCM2-7 activation might contribute to the molecular pathogenesis of drug resistance in SCLC cells.…”

Extracellular vesicle-mediated crosstalk between melanoma and the immune system: Impact on tumor progression and therapy response

“…Regarding targeted therapy, specifically BRAF inhibition, the participation of EVs as carriers of resistance mechanisms has been described by several studies. This could be achieved through the MITF‐dependent up‐regulation of miR‐211–5p in melanoma‐derived EVs, 86 or down‐regulation of exosomal miR‐3613‐3p and consequent up‐regulation of CDC7 in melanoma cells 87 as well as through transport of proteins that directly affect drug sensitivity such as the receptor tyrosine kinases PDGFRβ 88 and ALK 89 (Fig. 2).…”