# Effectiveness of PROTAC BET Degraders in Combating Cisplatin Resistance in Head and Neck Cancer Cells

## TL;DR

This study shows that BET degraders like ARV-825 can help overcome cisplatin resistance in head and neck cancer cells.

## Contribution

The study introduces BET degraders as a novel approach to combat cisplatin resistance in HNSCC.

## Key findings

- BET degraders ARV-825 and ARV-771 induced apoptotic cell death in both cisplatin-sensitive and resistant HNSCC cells.
- ARV-825 reduced BRD4, c-Myc, Survivin, and RAD51 expression, indicating disruption of DNA repair and survival pathways.
- The effectiveness of ARV-825 was independent of senescence induction, suggesting a non-senolytic mechanism.

## Abstract

Head and neck squamous cell carcinoma (HNSCC) remains challenging to treat despite multimodal therapeutic approaches. Cisplatin treatment is effective and cost-efficient, although chemoresistance and disease recurrence limit its efficacy. Understanding the mechanisms of cisplatin resistance and the identification of compounds to target resistant tumor cells are critical for improving patient outcomes. We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor that has senolytic properties. Here, we report the development of a cisplatin-resistant cell line (HN30R) for the testing of ABT-263 and the PROTAC BET degraders ARV-825 and ARV-771. ABT-263 was ineffective in sensitizing HN30R cells to cisplatin, largely due to a lack of senescence induction. However, the BET degraders in combination with cisplatin promoted apoptotic cell death in both HN30 and HN30R cells. The effectiveness of ARV-825 did not appear to depend on the cells entering into senescence, indicating that it was not acting as a conventional senolytic. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment.