Journal of Experimental Pharmacology (May 2021)
Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study
Abstract
Helena Pópulo,1– 3 Beatriz Domingues,1,2 Cristina Sampaio,1,2 José Manuel Lopes,1– 4 Paula Soares1– 3 1Institute of Molecular Pathology and Immunology, IPATIMUP, University of Porto, Porto, Portugal; 2Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; 3Department of Pathology, Medical Faculty, University of Porto, Porto, Portugal; 4Department of Pathology, Hospital São João, Porto, PortugalCorrespondence: Helena PópuloInstitute of Molecular Pathology and Immunology, IPATIMUP, University of Porto, Rua Júlio Amaral de Carvalho, 45, Porto, 4200-135, PortugalTel +351 225570700Fax +351 225570799Email [email protected]: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance.Methods: In this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested.Results: In general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA.Discussion and Conclusion: Our results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition.Keywords: melanoma, vemurafenib, cobimetinib, everolimus, DCA, metabolism
