Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecula...

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Published in:Cell reports (Cambridge) 2022-11, Vol.41 (6), p.111601-111601, Article 111601
Main Authors: Carotenuto, Pietro, Romano, Alessia, Barbato, Anna, Quadrano, Paola, Brillante, Simona, Volpe, Mariagrazia, Ferrante, Luigi, Tammaro, Roberta, Morleo, Manuela, De Cegli, Rossella, Iuliano, Antonella, Testa, Marialuisa, Andreone, Fabrizio, Ciliberto, Gennaro, Clery, Eduardo, Troncone, Giancarlo, Palma, Giuseppe, Arra, Claudio, Barbieri, Antonio, Capone, Mariaelena, Madonna, Gabriele, Ascierto, Paolo A., Lanfrancone, Luisa, Indrieri, Alessia, Franco, Brunella
Format: Article
Language:English
Subjects:
melanoma drug resistance, MAPK inhibitors, drug repositioning, MITF, APAF-1, epigenetic drugs, apoptosome, drug repositioning, apoptosome-independent cell death
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Summary:Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in vitro and in vivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma. [Display omitted] •The MITF/APAF-1 axis is a molecular driver of MAPK inhibitor resistance•QNC and MBZ are potent activators of apoptosome-independent cell death•QNC and MBZ act by inhibiting specific epigenetic modulators of MITF/APAF-1•QNC/MBZ with MAPK inhibitors: potential therapeutic approach for resistant melanoma Carotenuto et al. show that the MITF/APAF-1 axis is a molecular driver of MAPK inhibitor resistance in melanoma. Two compounds regulating key signaling networks in melanoma, including the MITF/APAF-1 axis, were identified. The identified therapeutic approach may represent an important clinical advance in the treatment of resistant melanoma.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.111601