Alectinib enhances response to RBM39 degradation via SRPK1 inhibition

Ma, Y.; Poon, E.; Jin, C.; Martins da Costa, B.; Xu, Y.; Quazi, S.; Zourdoumis, N.; Wickremesinghe, C.; Chesler, L.; Keun, H. C.; Nijhuis, A.

doi:10.1101/2025.03.28.644532

bioRxiv · 10.1101/2025.03.28.644532

Alectinib enhances response to RBM39 degradation via SRPK1 inhibition

Ma, Y.·Poon, E.·Jin, C.·Martins da Costa, B.·Xu, Y.·Quazi, S.·Zourdoumis, N.·Wickremesinghe, C.·Chesler, L.·Keun, H. C.·Nijhuis, A.

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Abstract

Precise control of pre-mRNA splicing is critical for transcriptome integrity, and its disruption is increasingly recognised as a vulnerability in cancer. Here, we identify a functional interplay between two key splicing regulators, RBM39 and serine/arginine protein kinase 1 (SRPK1), and show that dual targeting of these factors severely compromises splicing fidelity in high-risk neuroblastoma. We use the molecular glue indisulam to degrade RBM39 and repurpose the clinical ALK inhibitor alectinib which potently inhibits SRPK1. Co-treatment with indisulam and alectinib inhibited cell proliferation, induced apoptosis, and caused G2/M arrest in multiple cancer cell lines, including MYCN-amplified neuroblastoma. RNA sequencing revealed enhanced splicing defects preferentially in DNA repair and genome maintenance 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 tumour regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treat aggressive malignancies such as high-risk neuroblastoma, exploiting the previously untapped polypharmacology of alectinib as a clinical RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

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Ma, Y., Poon, E., Jin, C., Martins da Costa, B., Xu, Y., Quazi, S., Zourdoumis, N., Wickremesinghe, C., Chesler, L., Keun, H. C., Nijhuis, A.. 2025-03-28. Alectinib enhances response to RBM39 degradation via SRPK1 inhibition. https://doi.org/10.1101/2025.03.28.644532

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