American Association for Cancer Research
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Supplementary Figure S2 from Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

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journal contribution
posted on 2023-04-03, 21:02 authored by Miles A. Miller, Madeleine J. Oudin, Ryan J. Sullivan, Stephanie J. Wang, Aaron S. Meyer, Hyungsoon Im, Dennie T. Frederick, Jenny Tadros, Linda G. Griffith, Hakho Lee, Ralph Weissleder, Keith T. Flaherty, Frank B. Gertler, Douglas A. Lauffenburger

Supplementary Figure S2. Correlation between plasma RTK changes with MAPKi, PFS, and initial tumor shrinkage (using RECIST) in melanoma patients.



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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.Significance: 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. Cancer Discov; 6(4); 382–99. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 331

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