Abstract
Ammonium tetrathiomolybdate (TTM) and disulfiram (DSF) are copper (Cu) chelators in cancer clinical trials partly because Cu chelation: a) restricts the activity of Cu-binding MEK1/2 enzymes which drive tumourigenesis by KRAS or BRAF oncogenic mutations and b) enhances uptake of oxaliplatin (OxPt), clinically used in advanced KRAS-mutant colorectal carcinomas (CRC). Whereas TTM decreases intracellular Cu trafficking, DSF can reach other Cu-dependent intracellular proteins. Since the use of individual or combined Cu chelation may help or interfere with anti-cancer therapy, this study investigated whether TTM modifies the response to DSF supplemented with: 1) UO126, a known MEK1/2 inhibitor; 2) other Cu chelators like neocuproine (NC) or 1, 10-o-phenanthroline (OPT) in wt p53 melanoma cells differing in BRAF or KRAS mutations; 3) OxPt in mutant p53 CRC cells devoid of KRAS and BRAF mutations or harbouring either KRAS or BRAF mutations. TTM was not toxic against V600E-mut-BRAF A375 and G12D-mut-KRAS/high c-myc C8161 melanoma cells. Moreover, TTM protected both melanoma types from toxicity induced by DSF, NC and co-treatment with sub-lethal levels of DSF and the MEK inhibitor, UO126. Toxicity by co-treatment with DSF+OPT was poorly reversed by TTM in C8161 melanoma cells. In contrast to the greater toxicity of 0.1 μM DSF against mutant p53 CRC cells irrespective of their KRAS mutation, TTM did not protect G12V-mut-KRAS/high c-myc SW620 CRC from DSF+OxPt compared to KRAS-WT/BRAF-WT Caco-2 CRC. Our results show that DSF co-treatment with: a) MEK inhibitors may enhance tumour suppression; b) OxPt in CRC may counteract impaired response to cetuximab by KRAS/BRAF mutations and c) as a single treatment, TTM may be less effective than DSF and decreases the efficacy of the latter.HighlightsPotentiation of melanoma antitumour toxicity of DSF by MEK inhibitor is reversed by TTM.KRAS/c-MYC dysregulation attenuates TTM reversion of melanoma toxicity by DSF + OPT.KRAS/c-MYC dysregulation increases melanoma NC toxicity reversed by TTM.BRAF mutation and lower c-MYC may attenuate toxicity by DSF ± OxPt in colorectal cancer cells
Highlights
The copper (Cu) dependence of MEK1/2 dysfunctional signalling is an important target to inhibit tumour cells with BRAF or KRAS mutations [1, 2]
We investigated whether other Cu chelators or MEK inhibitors behaved like TTM or DSF in wt p53 melanomas differing in KRAS/c-MYC or BRAF status
Since both KRAS and BRAF mutations drive tumour cell proliferation by Cu-dependent MEK1/2 kinase activation through different responses in melanomas [4] or colorectal carcinomas ecancer 2019, 13:890 (CRC) [5], we studied the response to TTM and/or DSF in mutant p53 CRC with mutant KRAS [29] and high c-MYC [30] compared to CRC cells with a BRAF-mutant [29] low c-MYC [30] status and another mutant p53 CRC harbouring wt BRAF and wt KRAS [29]
Summary
The copper (Cu) dependence of MEK1/2 dysfunctional signalling is an important target to inhibit tumour cells with BRAF or KRAS mutations [1, 2]. TTM almost completely blocked DSF-Cuinduced cell death in SUM149 and rSUM149 inflammatory breast cancer cells, highlighting the importance of Cu binding for enhancement of DSF’s cytotoxic effects [20] Both DSF and TTM are Cu chelators, TTM decreases intracellular Cu trafficking [22], unlike DSF which can reach other Cu-dependent intracellular proteins [19, 22]. We investigated whether other Cu chelators or MEK inhibitors behaved like TTM or DSF in wt p53 melanomas differing in KRAS/c-MYC or BRAF status Since both KRAS and BRAF mutations drive tumour cell proliferation by Cu-dependent MEK1/2 kinase activation through different responses in melanomas [4] or colorectal carcinomas ecancer 2019, 13:890
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