Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study

Helena Pópulo; Beatriz Domingues; Cristina Sampaio; José Manuel Lopes; Paula Soares

doi:10.2147/JEP.S297831

Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study

J Exp Pharmacol. 2021 May 24:13:521-535. doi: 10.2147/JEP.S297831. eCollection 2021.

Authors

Helena Pópulo^{1

2

3}, Beatriz Domingues^{1

2}, Cristina Sampaio^{1

2}, José Manuel Lopes^{1

2

3

4}, Paula Soares^{1

2

3}

Affiliations

¹ Institute of Molecular Pathology and Immunology, IPATIMUP, University of Porto, Porto, Portugal.
² Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
³ Department of Pathology, Medical Faculty, University of Porto, Porto, Portugal.
⁴ Department of Pathology, Hospital São João, Porto, Portugal.

Abstract

Background: 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: DCA; cobimetinib; everolimus; melanoma; metabolism; vemurafenib.

Grants and funding

This work was supported by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This article received also funding from the project PTDC/MEC-ONC/31520/2017 (Predicting patients’ response to liposomal anticancer drugs: focusing on LRP1B endocytic activity) supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and FCT. The funders did not participate in study design, data collection and analysis, decision to publish, or preparation of the manuscript.