Exploiting the polypharmacology of alectinib for synergistic RNA splicing disruption with RBM39 degraders
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Precise control of pre-mRNA splicing is vital for transcriptome integrity, and its disruption is an emerging cancer vulnerability. Here, we use indisulam to degrade RBM39 and show that the clinical ALK inhibitor alectinib can be repurposed to inhibit SRPK1. Co-treatment of indisulam and alectinib inhibited cell proliferation, induced apoptosis, and caused cell-cycle arrest in multiple cancer cell lines, including MYCN-amplified high-risk neuroblastoma. RNA sequencing revealed enhanced splicing defects preferentially in DNA repair-related genes following combination treatment, leading to R-loop accumulation and increased DNA damage. In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumor regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treating aggressive malignancies such as high-risk neuroblastoma, exploiting the untapped polypharmacology of alectinib as an RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.
Date Issued
2026-01-27
Date Acceptance
2025-12-01
Citation
Cell reports, 2026, 45 (1)
ISSN
2211-1247
Publisher
Elsevier
Journal / Book Title
Cell reports
Volume
45
Issue
1
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1016/j.celrep.2025.116784
Publication Status
Published
Article Number
116784
Date Publish Online
2026-01-08