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 (NSCLCs) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBCs) and head and neck squamous cell carcinomas (HNSCCs) and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiation, and targeted therapy. Since 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.

Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

“…Recently, a study from our group demonstrated a potential new functional role of AXL in regulating DNA damage response in NSCLC, head and neck cancer, and triple-negative breast cancer models. In that study, the combination of AXL and PARP inhibitors was highly synergistic in cell lines (43). The current study builds upon these findings, highlighting a possible mechanism through which AXL may directly contribute to DDR inhibitor resistance.…”

The Use of Chemosensitizers to Enhance the Response to Conventional Therapy in Triple-Negative Breast Cancer Patients

“…Another recent study unveiled the involvement of an alternative pathway to PI3K, which caused a defect in the HR DNA repairing pathway and sensitized TNBC cell lines to PARP inhibition. The results shed light on the role played by the TAM family receptor tyrosine kinase AXL in epithelial-mesenchymal transition and, for the first time, HR DNA repair pathway, suggesting the use of AXL inhibitors as chemosensitizers in combination with PARP inhibitors in breast cancer [13]. Breast cancer patients with impairment in DNA damage response, HR proteins and BRCA1/2 all harbor a relatively high genomic instability and defective DNA repair machinery; subsequently, they became sensitive to DNA damaging agents such as, PARP inhibitors and platinum agents.…”

“…A relatively high incidence of germline mutations in the BRCA1/2 genes was reported in TNBCs patients which makes them more sensitive to DNA damaging agents such as platinum and PARP inhibitors, the last of which are particularly active in tumors with defects in DNA HR [1]. Studies provided evidence that targeting key signaling pathways could potentialize the therapeutic effects of the DNA damaging drugs [11][12][13]. The PI3K signaling pathway preserves HR steady state, thus the inhibition of PI3K pathway would result in HR impairment in BRCA-proficient TNBC patients and subsequently sensitize the carcinoma cells to PARP inhibitors.…”

The AP-1 complex regulates AXL expression and determines sensitivity to PI3Kα inhibition in esophagus and head and neck squamous cell carcinoma

“…This overexpression of AXL in response to therapy is not unique to these malignant diseases or to PI3K-targeting therapies, as AXL pathway activation has been reported in various cancers that developed resistance to radiotherapy, chemotherapies and EGFR inhibitors (15)(16)(17)(18)(19)(38)(39)(40). Indeed, small molecule inhibitors (such as therapies is superior to that of the monotherapies (15,40,(42)(43)(44)(45)(46)(47).…”