# Targeting the ANGPTL4/NRP1/ABL1/RAD51 axis reverses cisplatin resistance by impairing DNA damage repair in head and neck cancer

## TL;DR

This study identifies a new pathway involving ANGPTL4 and other proteins that helps head and neck cancer cells resist cisplatin, suggesting a potential new treatment strategy.

## Contribution

The paper reveals a novel molecular axis (ANGPTL4/NRP1/ABL1/RAD51) that drives cisplatin resistance in HNSCC.

## Key findings

- ANGPTL4 activates ABL1, which phosphorylates RAD51 to promote DNA repair in HNSCC cells.
- Inhibiting NRP1 or ABL1 reverses cisplatin resistance and increases cell death in HNSCC models.
- The ANGPTL4/NRP1/ABL1/RAD51 axis is a potential therapeutic target for overcoming chemoresistance.

## Abstract

Here, we identify a molecular pathway that drives cisplatin resistance in head and neck squamous cell carcinoma (HNSCC). The angiogenic factor angiopoietin-like 4 (ANGPTL4) engages Neuropilin1 to activate ABL1, which in turn phosphorylates and activates the DNA recombinase and homologous recombination protein, RAD51. This enables HNSCC cells to survive cisplatin-induced genotoxic stress. These results mechanistically demonstrate a role for ANGPTL4 and a cellular signaling axis to overcome chemoresistance in HNSCC. These findings also have potential implications for other ANGPTL4-overexpressing tumors.

Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr315/54 through an NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.