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Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9

Yang Fu1, Ge Yang2, Peipei Xue3,4

  • 11Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, 450052 Zhengzhou, China.

Cell Death Discovery
|May 31, 2018
PubMed

Insights

Dasatinib inhibits colon cancer cell death induced by 5-fluorouracil (5-FU) by blocking Src kinase activation, which is crucial for caspase-9 activity. This finding may explain why dasatinib and FOLFOX chemotherapy failed in metastatic colorectal cancer (mCRC) clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Preclinical studies suggested dasatinib inhibits colon cancer.
  • Clinical trials combining dasatinib with chemotherapy (FOLFOX) showed limited efficacy in metastatic colorectal cancer (mCRC).
  • The role of Src kinase inhibitors in combination cancer therapy remains unclear.

Purpose of the Study:

  • To investigate if dasatinib interferes with 5-fluorouracil (5-FU)-induced apoptosis in colon carcinoma.
  • To explore the mechanism by which dasatinib affects chemotherapy response in colon cancer.

Main Methods:

  • Western blotting to detect protein phosphorylation.
  • Assays to measure caspase-9 activity.
  • Cellular apoptosis assays in colon carcinoma models.

Main Results:

  • Src kinase directly phosphorylates caspase-9 at tyrosine 251, enhancing its activity.
  • Dasatinib treatment suppressed Src activation.
  • Dasatinib significantly reduced 5-FU-triggered apoptosis in colon carcinoma cells by inhibiting Src activation.

Conclusions:

  • Dasatinib interferes with 5-FU-induced apoptosis in colon cancer by suppressing Src kinase.
  • Src kinase activation is essential for 5-FU-induced apoptosis via caspase-9.
  • The findings provide a potential explanation for the clinical failure of dasatinib-FOLFOX combination therapy in mCRC.

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