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Ref Type Journal Article
PMID (27671334)
Authors Balaji K, Vijayaraghavan S, Diao L, Tong P, Fan Y, Carey JP, Bui TN, Warner S, Heymach JV, Hunt KK, Wang J, Byers LA, Keyomarsi K
Title AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer research : MCR 15 1 2017 Jan 45-58 Mol Cancer Res
URL
Abstract Text 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AXL positive triple-receptor negative breast cancer sensitive Bemcentinib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, an AXL-expressing triple-receptor negative breast cancer cell line demonstrated greater sensitivity to the combination of Bemcentinib (BGB-324) and Lynparza (olaparib) compared to either agent alone in culture, resulting in a highly synergistic effect (PMID: 27671334). 27671334
AXL positive head and neck squamous cell carcinoma sensitive Dubermatinib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line expressing AXL demonstrated greater sensitivity to the combination of Dubermatinib (TP-0903) and Lynparza (olaparib) compared to either agent alone in culture, resulting in decreased colony formation, inhibition of cell growth, and increased apoptotic activity (PMID: 27671334). 27671334
AXL positive triple-receptor negative breast cancer sensitive Dubermatinib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, a triple-receptor negative breast cancer cell line expressing AXL demonstrated greater sensitivity to the combination of Dubermatinib (TP-0903) and Lynparza (olaparib) compared to either agent alone in culture, resulting in decreased colony formation, inhibition of cell growth, and increased apoptotic activity (PMID: 27671334). 27671334
AXL positive lung non-small cell carcinoma sensitive Bemcentinib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, an AXL-expressing non-small cell lung carcinoma cell line demonstrated greater sensitivity to the combination of BGB-324 and Lynparza (olaparib) compared to either agent alone in culture, resulting in a highly synergistic effect (PMID: 27671334). 27671334
AXL positive lung non-small cell carcinoma sensitive Dubermatinib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung carcinoma cell line expressing AXL demonstrated greater sensitivity to the combination of Dubermatinib (TP-0903) and Lynparza (olaparib) compared to either agent alone in culture, resulting in decreased colony formation, inhibition of cell growth, and increased apoptotic activity (PMID: 27671334). 27671334