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

Abstract

Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance, and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non-small cell lung cancers (NSCLC) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBC) and head and neck squamous cell carcinomas (HNSCC), and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiotherapy, and targeted therapy. Because the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes, and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC, and NSCLC patient cohorts.

IMPLICATIONS:

The novel role for AXL in DNA repair, linking it to EMT, suggests that AXL can be an effective therapeutic target in combination with targeted therapy such as PARP inhibitors in several different malignancies. Mol Cancer Res; 15(1); 45-58. ©2016 AACR.

• Authors: Kavitha Balaji, Smruthi Vijayaraghavan, Lixia Diao, Pan Tong, Youhong Fan, Jason Pw Carey, Tuyen N Bui, Steve Warner, John V Heymach, Kelly K Hunt, Jing Wang, Lauren Averett Byers, Khandan Keyomarsi
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 15 Issue 1 Pg. 45-58 (01 2017) ISSN: 1557-3125 [Electronic] United States
• PMID: 27671334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• Proto-Oncogene Proteins
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• DNA Damage
• DNA Repair (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Neoplasms (enzymology, pathology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Axl Receptor Tyrosine Kinase