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

by Selleckchem | Oct 26 2023

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.

Comments:

Your research findings highlight the role of cellular plasticity and adaptations in driving the recurrence of glioblastoma (GBM) during standard-of-care chemotherapy with temozolomide (TMZ). To investigate these adaptations, you performed in vivo single-cell RNA sequencing on patient-derived xenograft (PDX) tumors of GBM before, during, and after TMZ therapy. This analysis revealed distinct cellular populations present during TMZ treatment, with a particular focus on the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2).

The increased expression of RRM2 was found to regulate the production of dGTP and dCTP, which are essential for the DNA damage response during TMZ therapy. Your multidimensional modeling approach, combining spatially resolved transcriptomic and metabolomic analysis in patients' tissues, demonstrated strong correlations between RRM2 expression and dGTP levels. This supports the notion that RRM2 plays a role in regulating the demand for specific deoxyribonucleotide triphosphates (dNTPs) during therapy.

Furthermore, you investigated the potential therapeutic implications of targeting RRM2. Treatment with the RRM2 inhibitor 3-AP (Triapine) was found to enhance the efficacy of TMZ therapy in PDX models, suggesting that inhibiting RRM2-mediated nucleotide production could be a promising strategy to overcome chemoresistance in GBM.

In summary, your research provides novel insights into the mechanisms underlying chemoresistance in GBM, specifically highlighting the critical role of RRM2-mediated nucleotide production. By identifying and targeting this pathway, there is potential to improve the effectiveness of TMZ therapy in treating GBM.