Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

• Published in: Cancer discovery 2016-04, Vol.6 (4), p.382-399
• Main Authors: Miller, Miles A, Oudin, Madeleine J, Sullivan, Ryan J, Wang, Stephanie J, Meyer, Aaron S, Im, Hyungsoon, Frederick, Dennie T, Tadros, Jenny, Griffith, Linda G, Lee, Hakho, Weissleder, Ralph, Flaherty, Keith T, Gertler, Frank B, Lauffenburger, Douglas A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Membrane - metabolism; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Female; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - mortality; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Models, Biological; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational; Proteolysis; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-jun; Receptor Protein-Tyrosine Kinases - blood; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-15-0933

Kinase inhibitor resistance often involves upregulation of poorly understood "bypass" signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance. Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action.