Journal
MOLECULAR CANCER RESEARCH
Volume 15, Issue 1, Pages 45-58Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0157
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Funding
- NIH [CA016672, CA87548, CA1522218]
- Susan G. Komen [KG100521]
- LUNGevity Foundation
- MDACC Physician Scientist Program
- MDACC R. Lee Clark Fellow Award
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for the Personalized Cancer Therapy's (IPCT's) Center for Professional Education and Training
- University of Texas SPORE in Lung Cancer [5P50 CA070907-10]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP140106]
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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. (C) 2016 AACR.
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