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Cabozantinib inhibits AXL- and MET-dependent cancer cell migration induced by growth-arrest-specific 6 and hepatocyte

Takahito Hara1, Akiko Kimura2, Tohru Miyazaki3

  • 1Innovation Promotion, Shonan Research Central Office, Research, Takeda Pharmaceutical Company Limited, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa, 251-8555, Japan.

Biochemistry and Biophysics Reports
|February 15, 2020
PubMed

Insights

Cabozantinib inhibits cancer cell migration and invasion by targeting both AXL and MET pathways. This dual inhibition is crucial for its anti-cancer effects, as blocking either pathway alone is less effective.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Cabozantinib targets receptor tyrosine kinases including AXL and MET.
  • AXL and MET ligands, GAS6 and HGF, promote cancer cell proliferation and metastasis.
  • The precise mechanism of cabozantinib's action on AXL and MET in cancer cell migration remains unclear.

Purpose of the Study:

  • To investigate how cabozantinib regulates cancer cell migration and invasion via AXL and MET signaling.
  • To elucidate the independent and combined roles of GAS6-AXL and HGF-MET pathways in cancer cell motility.

Main Methods:

  • Boyden chamber assays to assess cancer cell migration.
  • Short interfering RNA (siRNA) to knock down AXL and MET expression.
  • Western blotting to analyze protein phosphorylation (AXL, MET, SRC) in response to cabozantinib treatment.

Main Results:

  • GAS6 and HGF individually induced migration in SKOV3 cells, with a combined additive effect.
  • siRNA-mediated knockdown of AXL and MET individually reduced ligand-induced migration; double knockdown abolished it.
  • Cabozantinib inhibited AXL, MET, and SRC phosphorylation, suppressing GAS6/HGF-induced migration and invasion, unlike capmatinib.

Conclusions:

  • The GAS6-AXL and HGF-MET signaling pathways independently drive cancer cell migration and invasion.
  • Simultaneous inhibition of both AXL and MET pathways by cabozantinib is key to its anti-cancer efficacy.
  • Cabozantinib's dual-targeting mechanism offers a promising therapeutic strategy against metastatic cancers.
Keywords:
AXL receptor tyrosine kinaseCabozantinibCancer cell migrationGrowth arrest-specific 6Hepatocyte growth factorMET proto-oncogene-encoded receptor tyrosine kinase

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