Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production

Ella N. Perrault, Jack M. Shireman, Eunus S. Ali, Peiyu Lin, Isabelle Preddy, Cheol Park, Shreya Budhiraja, Shivani Baisiwala, Karan Dixit, C. David James, Dieter H. Heiland, Issam Ben-Sahra, Sebastian Pott, Anindita Basu, Jason Miska, Atique U. Ahmed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients' tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models.We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.

Original languageEnglish (US)
Article numbereade7236
JournalScience Advances
Volume9
Issue number20
DOIs
StatePublished - 2023

ASJC Scopus subject areas

  • General

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