Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression. To overcome this disease, many investigators attempted to solve the problem of BRAF-inhibitor resistance leading to medically ineffective treatment.
Sensitive and resistance to BRAF inhibition in melanoma
A research indicates that the root of resistance to BRAF inhibitors may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors in many cases. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine (HCQ), and the BRAF inhibitors will be able to do their job better.
Another research interprets why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’. According to analysis, 6 out of 16 melanoma tumours acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Suppression of sex determining region Y-box 10 (SOX10) in melanoma is found to cause activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. Additionally, investigators find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples.
With the application of value, Moffitt researchers found that using two inhibitors (Mekinist [trametinib] and Tafinlar[dabrafenib]) to block different growth pathways during treatment prevented resistance in patients with BRAF mutation. The combination of these two inhibitors, as a newly FDA-approved therapy, is one of the biggest advancements in melanoma treatment in the past 30 years. From a clinical perspective, 76 percent of patients achieve success in the treatment of the Mekinist and Tafinlar combination, and this therapy reduces the incidence and severity of some of the toxic effects patients experience when the drugs is used alone.
Reference:
1. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014 Apr 3;508(7494):118-22.
2. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. New England Journal of Medicine, 2012; 367 (18): 1694 DOI: 10.1056/NEJMoa1210093
3. Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI70454