TY  - JOUR
AU  - Perrault, Ella N
AU  - Shireman, Jack M
AU  - Ali, Eunus S
AU  - Lin, Peiyu
AU  - Preddy, Isabelle
AU  - Park, Cheol
AU  - Budhiraja, Shreya
AU  - Baisiwala, Shivani
AU  - Dixit, Karan
AU  - James, C David
AU  - Heiland, Dieter H
AU  - Ben-Sahra, Issam
AU  - Pott, Sebastian
AU  - Basu, Anindita
AU  - Miska, Jason
AU  - Ahmed, Atique U
TI  - Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production.
JO  - Science advances
VL  - 9
IS  - 20
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2023-01004
SP  - eade7236
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37196077
DO  - DOI:10.1126/sciadv.ade7236
UR  - https://inrepo02.dkfz.de/record/276104
ER  -