Stopping resistance to targeted therapy- nelfinavir- for BRAF and NRAS mutant melanoma

Targeted therapy can provide a rapid response, leaving melanoma patients with minimal tumors or even NED.  The problem has been that all too often those tumors learn to work around the positive effects of the drugs and come back raring to go.  Adding MEK inhibitors to BRAF inhibitors combined with alternate dosing schedules have done much to minimize side effects and tumor resistance.  However, resistance remains a problem.  Here articles address two new methods to deal with BRAFi resistance:  BRAFi and SRS is a good combo in brain mets AND BRAFi resistant tumors may be vulnerable to arginine deprivation or resistance avoided with the addition of APR-246

And here's one more: 

Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.  Smith, Brunton, Rowling, et al. Cancer Cell. 2016 Mar 14.

Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.

Wishing you all my best - c