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Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer

Na Song1, Xiujuan Qu1, Shizhou Liu2

  • 1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Experimental and Therapeutic Medicine
|August 17, 2017
PubMed

Insights

Combining MET and SRC kinase inhibition shows promise for colorectal cancer (CRC) treatment. This dual approach effectively reduces colon cancer cell viability and enhances apoptosis, outperforming single-target therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Hepatocyte growth factor (HGF)/MET signaling is crucial in colorectal cancer (CRC) development and offers therapeutic potential.
  • Inhibiting MET alone has shown limited efficacy in treating various cancers, necessitating exploration of alternative strategies.

Purpose of the Study:

  • To investigate the combined inhibition of MET and SRC kinase activity in colon cancer cells.
  • To elucidate the role of the HGF/MET pathway in both ligand-dependent and -independent activation.
  • To evaluate the therapeutic potential of concurrent MET and SRC inhibition in CRC.

Main Methods:

  • Small interfering RNA (siRNA) and inhibitors were used to assess single and combined inhibition effects.
  • Western blotting was employed to analyze protein phosphorylation levels (SRC, AKT, ERK).
  • Cell viability and apoptosis assays were conducted on colon cancer cells with mutant and wild-type RAS.

Main Results:

  • Single MET inhibition showed limited anti-viability effects and did not inhibit basal SRC, AKT, or ERK phosphorylation.
  • SRC activation was essential for both ligand-dependent and -independent MET activation, as SRC inhibition (dasatinib) suppressed MET activation and downstream signaling.
  • Combined MET and SRC inhibition significantly enhanced viability inhibition and apoptosis in colon cancer cells, irrespective of RAS mutation status.

Conclusions:

  • SRC kinase activity is integral to both ligand-dependent and -independent MET activation in colon cancer.
  • Concurrent inhibition of MET and SRC kinase presents a promising therapeutic strategy for colorectal cancer.
  • This combination therapy demonstrates superior efficacy compared to single-target inhibition, offering a potential new avenue for CRC treatment.
Keywords:
METSRCcolon cancertargeted therapy

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