Miller, Oudin, and colleagues showed that treatment with MEK inhibitors resulted in reduced levels of circulating receptor tyrosine kinases (RTK), increased tumor expression of RTKs, and decreased metalloproteinase activity. Circulating RTK levels were correlated with progression-free survival in patients with melanoma and kinase inhibitor resistance. MEK inhibitor treatment promoted the association of tissue inhibitor of metalloproteinase 1 (TIMP1) with metalloproteinases to induce the accumulation of AXL on the cell surface and subsequently drive the activation of JNK bypass signaling. These findings identify a bypass mechanism by which kinase inhibitors reduce proteolytic shedding of surface receptors and show that kinase inhibitor resistance may be overcome by neutralizing TIMP1 or the addition of a bypass RTK inhibitor. For details, please see the article by Miller, Oudin, and colleagues on page 382.