Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma

Authors

• AJ Issak
• GR Clements L Huang
• Y Qin
• Q Zho
• G Merlino
• Y Yu

Abstract

A primary cause of melanoma in patients is a mutation of the BRAF protein in the MAPK signaling pathway. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence due to acquired drug resistance continue to be urgent clinical issues. Preclinical studies have suggested concurrent inhibition of BRAF and MEK using inhibitors (BRAFi and MEKi) to block hyperactivated MAPK signaling. However, most patients treated with this combination therapy still relapse due to acquired resistance. Extending our studies to examine the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down or inhibition in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. Our findings uncover the mechanism of how melanoma cells escape BRAFi and MEKi attacks and offer a rational strategy to guide clinical treatment.

Scientific Focus Area: Cancer Biology

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