NF1 loss leads to Ras/rapidly accelerated fibrosarcoma (RAF)/mitogen activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) activation (3), and the MEK inhibitor selumetinib is approved for NF-1 associated pNFs (4, 5), yet selumetinib resistance through both Ras dependent and Ras independent mechanisms (6) remains an unmet challenge. The gene discussed is NF1; the disease is fibrosarcoma.