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bioRxiv · 10.64898/2026.06.15.732403

DNA Polymerase Beta Catalytic and Fidelity Mutations Drive Platinum Specific Drug Sensitivity

Lindquist, J.·Heyza, J.·Ndoja, I.·Movahhedin, N.·Yunker, C.·Cardo-Vila, M.·Kim, S.·Sweasy, J.·Patrick, S.
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Abstract

With the advent of genome sequencing and its widespread use in the clinic, there is a great need to identify mutational biomarkers that predict therapeutic responses. DNA polymerase Beta (Pol{beta}) and the base excision repair (BER) pathway have been previously implicated as modulators of response to platinum-based chemotherapies and are mutated in as high as 30% of cancers. Here, we show in a triple-negative breast cancer (TNBC) model that two classes of mutations in Pol{beta}, reduced catalytic activity (E295K and D256A mutation) and reduced fidelity (I260M), are sufficient to drive cisplatin and carboplatin-specific sensitivity. Cellular response to oxaliplatin in these Pol{beta} mutant models is minimal relative to cisplatin and carboplatin. Additionally, we show that sensitivity is associated with reduced repair of both platinum-induced DNA intrastrand adducts and interstrand crosslinks (ICLs). Downregulation of the upstream BER factor uracil DNA glycosylase (UNG) reverses drug sensitivity consistent with these Pol{beta} mutations negatively impacting ICL DNA repair to drive drug sensitivity. In addition, intrastrand adduct repair readout indicates these lesions also play a role in the sensitivity observed in Pol{beta} mutant models. In vivo studies demonstrate a significant effect on tumor growth delay with cisplatin treatment in tumor xenografts harboring Pol{beta} mutations. These results support the potential for using Pol{beta} mutations as predictive biomarkers for cisplatin and carboplatin therapies in the clinical setting.

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Lindquist, J., Heyza, J., Ndoja, I., Movahhedin, N., Yunker, C., Cardo-Vila, M., Kim, S., Sweasy, J., Patrick, S.. 2026-06-19. DNA Polymerase Beta Catalytic and Fidelity Mutations Drive Platinum Specific Drug Sensitivity. https://doi.org/10.64898/2026.06.15.732403

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