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Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair

Abstract

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.

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Fig. 1: Different damaging agents activate the DDR pathway in MM cells carrying activated IKKα(p45).
Fig. 2: BRAF inhibition prevents ATM and DDR activation in response to DNA damage-based treatments.
Fig. 3: Combination of DNA damaging agents with BRAF inhibitors imposes irreversible DNA damage and tumor cell eradication in vitro.
Fig. 4: In vivo eradication of MM cells by combination treatment using TMZ plus Vemurafenib.

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Acknowledgements

We want to thank the Bigas’ and Espinosa’s lab members for constructive discussions and suggestions and technical support. This work was funded by grants from Instituto de Salud Carlos III FEDER PI19/00013 to LE, PI19/01320 to AV and PI19/01210 to JM-L, Generalitat de Catalunya 2017SGR135 and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC) and Fundacion hna to AV research team in the development of orthoxenografts/PDOX. JA-M is a recipient of Javier Lamas Miralles grant.

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Correspondence to Alberto Villanueva, Anna Bigas, Fernando Gallardo or Lluís Espinosa.

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Alonso-Marañón, J., Villanueva, A., Piulats, J.M. et al. Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair. Oncogene 40, 5042–5048 (2021). https://doi.org/10.1038/s41388-021-01879-2

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