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Cancer Discov. 2016 Apr;6(4):382-99. doi: 10.1158/2159-8290.CD-15-0933. Epub 2016 Mar 16.

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

Author information

1
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
2
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
3
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
4
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
5
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
6
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
7
Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
8
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
9
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. lauffen@mit.edu.

Abstract

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.

PMID:
26984351
PMCID:
PMC5087317
DOI:
10.1158/2159-8290.CD-15-0933
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Potential Conflicts of Interest: No potential conflicts of interest were disclosed.

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