Qiang Zuo,Yanlin Yu,
PTEN Status Alters the Molecular Route to Resistance to BRAF Inhibitor in Melanoma
Clinical Oncology and Research
2019
2613-4942
http://dx.doi.org/10.31487/j.COR.2019.04.06
https://www.sciencerepository.org/pten-status-alters-the-molecular-route-to-resistance-to-braf-inhibitor-in-melanoma_COR-2019-4-106 
Abstract: Although targeted treatment by BRAF inhibitors (BRAFi) achieved a remarkable clinical response for patients with BRAF mutation, the strength of efficacy is short and limited by acquired drug resistance [1]. Recent studies identified many mechanisms of acquired resistance to BRAFi, such as mutations in NRAS or MEK1 and overexpression of COT, EGFR, PDGFRβ, IGF1R or MET, lead the reactivation of MAPK pathway and drive the cell proliferation, suggesting that co-targeting this hyperactivated survival pathway by combination inhibitors might gain the maximum clinical benefits for melanoma patients. Based on these findings, FDA approved the combination of dabrafenib (BRAFi) with trametinib (MEK inhibitor) or vemurafenib (BRAFi) with cobimetinib (MEK inhibitor) to inhibit the MAPK signaling pathway in 2014 and 2015 more effectively. Indeed, the dual inhibitors of MEK and mutant BRAF kinases have shown a higher overall survival rate and exciting results in initial tumor response in clinical. Moreover, this combinational treatment can prevent or delays the acquired resistance. However, the benefit of the combination did not last too long due to anew therapy resistance, which continues to obstacle the clinical applications. Novel strategies and molecular mechanism are therefore needed to improve the precision and efficiency of targeted therapy for resistant melanomaKeywords: PTEN, BRAF inhibitor, resistance, AXL, BRAF mutant melanoma