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Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
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Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal

Yuuki Obata1, Keita Horikawa1, Isamu Shiina2

  • 1Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda 278-0022, Chiba, Japan.

Cancer Letters
|December 3, 2017
PubMed

Insights

A novel drug, M-COPA, targets endoplasmic reticulum-retained Kit mutants in gastrointestinal stromal tumors (GISTs). This approach suppresses oncogenic signaling, offering a new strategy for imatinib-resistant GIST treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Gastrointestinal stromal tumors (GISTs) often harbor activating Kit tyrosine kinase mutations.
  • Imatinib therapy is effective but resistance develops due to secondary Kit mutations.
  • Previously, we identified Kit mutants localizing oncogenic signals to the Golgi apparatus in GISTs.

Purpose of the Study:

  • To investigate the efficacy of 2-methylcoprophilinamide (M-COPA) in suppressing oncogenic signaling in GIST.
  • To elucidate the mechanism by which M-COPA affects Kit kinase activity and localization.
  • To explore M-COPA as a potential therapeutic strategy for imatinib-resistant GIST.

Main Methods:

  • Treatment of GIST cells with M-COPA, an inhibitor of protein trafficking from the endoplasmic reticulum (ER) to the Golgi.
  • Assessment of Kit autophosphorylation status at specific tyrosine residues (Y703/Y721/Y730/Y936) using biochemical assays.
  • Analysis of protein tyrosine phosphatase (PTP) involvement in Kit dephosphorylation.
  • Evaluation of M-COPA's effect on imatinib-resistant GIST proliferation.

Main Results:

  • M-COPA treatment suppressed Kit autophosphorylation at Y703/Y730/Y936 in the ER, blocking oncogenic signaling.
  • ER-retained Kit Y703/Y730/Y936 were dephosphorylated by PTPs, rendering them inactive.
  • M-COPA inhibited the activation of Kit kinase domain mutants, suppressing imatinib-resistant GIST proliferation.

Conclusions:

  • Kit autophosphorylation is spatio-temporally regulated within the cell.
  • M-COPA effectively inhibits oncogenic Kit signaling by retaining and dephosphorylating mutants in the ER.
  • M-COPA represents a promising new therapeutic strategy for imatinib-resistant GISTs.
Keywords:
GISTGolgi apparatusImatinibKit tyrosine kinaseM-COPA

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