AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers
作者： Kavitha Balaji , Smruthi Vijayaraghavan , Lixia Diao , Pan Tong , Youhong Fan
DOI: 10.1158/1541-7786.MCR-16-0157
关键词: PARP1 、 AXL receptor tyrosine kinase 、 DNA Repair Pathway 、 Cancer research 、 DNA damage 、 Epithelial–mesenchymal transition 、 Cancer cell 、 Biology 、 Targeted therapy 、 DNA repair
摘要: Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance, metastasis. The mechanistic role upstream mediators EMT has not yet been well characterized. Recently, we showed that non–small cell lung cancers (NSCLC) have undergone overexpress AXL, receptor tyrosine kinase. AXL also overexpressed subset triple-negative breast (TNBC) head neck squamous carcinomas (HNSCC), its overexpression more aggressive tumor behavior linked resistance chemotherapy, radiotherapy, targeted therapy. Because the DNA repair pathway altered patient specimens overexpressing it hypothesized modulation cells will sensitize them agents targeting pathway. Downregulation or inhibition directly reversed phenotype, led decreased expression genes, diminished efficiency homologous recombination (HR) RAD51 foci formation. As result, caused state HR deficiency making sensitive protein, PARP1. synergized PARP inhibition, leading apoptotic death. positively markers across TNBC, HNSCC, NSCLC cohorts. Implications: novel for repair, linking EMT, suggests can be an effective therapeutic target combination therapy such as inhibitors several different malignancies. Mol Cancer Res; 15(1); 45–58. ©2016 AACR.
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