Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.

Nair, S. J.; Krishnaraj, A.; Wei, X.; Thakral, R.; Guo, W.; Subramanian, S. B.; Zhang, X.; Alley, K. R.; Feng, A.; Hoy, A.; Kung, D.; Tiwari, P. B.; Uren, A.; Maillard, R.; DeRose, V. J.

doi:10.64898/2025.12.20.694502

bioRxiv · 10.64898/2025.12.20.694502

Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.

Nair, S. J.·Krishnaraj, A.·Wei, X.·Thakral, R.·Guo, W.·Subramanian, S. B.·Zhang, X.·Alley, K. R.·Feng, A.·Hoy, A.·Kung, D.·Tiwari, P. B.·Uren, A.·Maillard, R.·DeRose, V. J.

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Abstract

Off-target interactions frequently compromise the clinical utility of anticancer agents by driving dose-limiting toxicity and therapeutic resistance. Although RNA has been predicted to be an off-target for numerous FDA-approved drugs, the extent and functional significance of RNA off-targeting among anticancer small molecules remain poorly understood. Using a systematic drug-binding screen, we identified cisplatin, a frontline chemotherapeutic that acts canonically through DNA adduct formation, as a prominent RNA binder. We employed cisplatin as a model compound to characterize the mechanistic basis and functional impact of RNA-small molecule off-targeting. To map transcriptome-wide cisplatin-RNA interactions, we developed PlatRNA-seq, a click-chemistry-enabled RNA-binding profiling platform. Genomic and functional analyses reveal that cisplatin preferentially accumulates at RNA G-quadruplex (rG4) structures near 5' transcript ends, inducing R-loop formation. Critically, we demonstrate that cisplatin cytotoxicity is partially mediated through RNA binding, revealing a noncanonical mechanism of action. Collectively, these findings illustrate the functional consequences of RNA-small-molecule off-targeting and provide a generalizable framework for investigating small-molecule-RNA interactions, opening new avenues for therapeutic innovation.

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Nair, S. J., Krishnaraj, A., Wei, X., Thakral, R., Guo, W., Subramanian, S. B., Zhang, X., Alley, K. R., Feng, A., Hoy, A., Kung, D., Tiwari, P. B., Uren, A., Maillard, R., DeRose, V. J.. 2025-12-23. Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.. https://doi.org/10.64898/2025.12.20.694502

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