Abstract C03: Role of human endogenous retrovirus-K in phenotype-switching of metastatic melanoma cells during microenvironment alterations

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

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

Scientific Reports ◽

10.1038/s41598-019-50732-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Shaimaa A. Gad ◽

Hamdy E. A. Ali ◽

Rofaida Gaballa ◽

Rania M. Abdelsalam ◽

Mourad Zerfaoui ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Clinical Effect ◽

Specific Inhibitor ◽

Melanoma Cells ◽

Development Of Resistance ◽

Dual Targeting ◽

Low Concentrations ◽

Resistant Cells

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.

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