# RBM39 Contributes to MGMT Maintenance in Response to Temozolomide-Induced DNA Damage

## TL;DR

This study shows that reducing RBM39 lowers MGMT levels, making cancer cells more sensitive to temozolomide, suggesting a new approach to treat resistant tumors.

## Contribution

The study identifies RBM39 as a regulator of MGMT and proposes co-targeting both to overcome chemoresistance.

## Key findings

- Pharmacological or genetic depletion of RBM39 reduces MGMT protein levels in cancer cells.
- Combining RBM39 degrader Indisulam with MGMT inhibitor O6-BG enhances MGMT depletion and increases cancer cell apoptosis.
- Co-targeting RBM39 and MGMT improves sensitivity to temozolomide in neuroendocrine tumor cells.

## Abstract

O6-Methylguanine-DNA methyltransferase (MGMT) is a key DNA repair enzyme that protects genomic stability by removing alkyl adducts from the O6 position of guanine. Available data indicate that the elevated MGMT expression in glioblastoma and neuroendocrine neoplasms is associated with resistance to alkylating agents such as temozolomide (TMZ). In this study, we investigated the effect of RBM39 on MGMT expression, based on preliminary observations suggesting a potential connection between these two proteins. Pharmacological or knockdown depletion of RBM39 led to a significant reduction in MGMT protein levels and increased sensitivity of cancer cells to TMZ. Moreover, the combination of Indisulam, a pharmacological degrader of RBM39, with the MGMT inhibitor O6-benzylguanine (O6-BG) resulted in enhanced MGMT depletion. These findings suggest that co-targeting RBM39 and MGMT may represent a promising strategy to overcome chemoresistance in tumors with high MGMT activity.

Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly increased apoptosis and decreased clonogenic growth in neuroendocrine tumor cells. These findings identify MGMT as a downstream target of RBM39 in MGMT-expressing cancer cells and highlight the therapeutic potential of co-targeting RBM39 and MGMT to overcome resistance to alkylating chemotherapy.