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AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Kavitha Balaji1, Smruthi Vijayaraghavan1, Lixia Diao2

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, Texas 77030.

Molecular Cancer Research : MCR
|September 28, 2016
PubMed

Insights

Inhibiting AXL receptor tyrosine kinase reverses cancer cell EMT, reduces DNA repair, and sensitizes tumors to PARP inhibitors, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Epithelial to mesenchymal transition (EMT) in cancer is linked to stemness, drug resistance, and metastasis.
  • AXL receptor tyrosine kinase is overexpressed in aggressive Non-Small Cell Lung Cancer (NSCLC), Triple-Negative Breast Cancer (TNBC), and Head and Neck Squamous Cell Carcinomas (HNSCC).
  • AXL overexpression correlates with aggressive tumor behavior and resistance to various cancer therapies.

Purpose of the Study:

  • To investigate the mechanistic role of AXL in mediating EMT and its connection to DNA repair pathways.
  • To determine if modulating AXL can sensitize cancer cells to DNA repair targeting agents.
  • To evaluate the therapeutic potential of combining AXL inhibition with PARP inhibitors.

Main Methods:

  • Studied the effect of AXL downregulation or inhibition on EMT phenotype and DNA repair gene expression.
  • Assessed homologous recombination (HR) efficiency and RAD51 foci formation after AXL modulation.
  • Investigated the synergistic effect of AXL inhibition and PARP1 inhibition on cancer cell apoptosis.

Main Results:

  • Downregulation or inhibition of AXL reversed the EMT phenotype in cancer cells.
  • AXL inhibition decreased the expression of DNA repair genes and diminished homologous recombination (HR) efficiency.
  • AXL inhibition induced HR deficiency, sensitizing cells to PARP1 inhibitors and leading to synergistic apoptotic cell death.

Conclusions:

  • AXL plays a crucial role in DNA repair, linking it to EMT.
  • AXL inhibition effectively reverses EMT and creates a state of HR deficiency.
  • Combining AXL inhibition with PARP inhibitors presents a promising therapeutic strategy for multiple cancer types, including NSCLC, TNBC, and HNSCC.

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