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

Perrault EN, Shireman JM, Ali ES, Lin P, Preddy I, Park C, Budhiraja S, Baisiwala S, Dixit K, James CD, Heiland DH, Ben-Sahra I, Pott S, Basu A, Miska J, Ahmed AU (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Science Advances American Association for the Advancement of Science

Book Volume: 9

Article Number: eade7236

Journal Issue: 20

DOI: 10.1126/sciadv.ade7236

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.

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Northwestern University US United States (USA) (US) University of Chicago US United States (USA) (US)

How to cite

APA:

Perrault, E.N., Shireman, J.M., Ali, E.S., Lin, P., Preddy, I., Park, C.,... Ahmed, A.U. (2023). Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production. Science Advances, 9(20). https://dx.doi.org/10.1126/sciadv.ade7236

MLA:

Perrault, Ella N., et al. "Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production." Science Advances 9.20 (2023).

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