RT Journal Article
SR Electronic
T1 Ribonucleotide Reductase Regulatory Subunit M2 as a Driver of Glioblastoma TMZ-Resistance through Modulation of dNTP Production
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.23.469785
DO 10.1101/2021.11.23.469785
A1 Ella N Perrault
A1 Jack M Shireman
A1 Eunus S Ali
A1 Isabelle Preddy
A1 Peiyu Lin
A1 Cheol Park
A1 Luke Tomes
A1 Andrew J Zolp
A1 Shreya Budhiraja
A1 Shivani Baisiwala
A1 C. David James
A1 Issam Ben-Sahra
A1 Sebastian Pott
A1 Anindita Basu
A1 Atique U Ahmed
YR 2021
UL http://biorxiv.org/content/early/2021/11/24/2021.11.23.469785.abstract
AB Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies have examined primary and recurrent GBM tumors, but it is difficult to study tumor evolution during therapy where resistance develops. To investigate this, we performed an in vivo single-cell RNA sequencing screen in a patient-derived xenograft (PDX) model. Primary GBM was modeled by mice treated with DMSO control, recurrent GBM was modeled by mice treated with temozolomide (TMZ), and during therapy GBM was modeled by mice euthanized after two of five TMZ treatments. Our analysis revealed the cellular population present during therapy to be distinct from primary and recurrent GBM. We found the Ribonucleotide Reductase gene family to exhibit a unique signature in our data due to an observed subunit switch to favor RRM2 during therapy. GBM cells were shown to rely on RRM2 during therapy causing RRM2-knockdown (KD) cells to be TMZ-sensitive. Using targeted metabolomics, we found RRM2-KDs to produce less dGTP and dCTP than control cells in response to TMZ (p<0.0001). Supplementing RRM2-KDs with deoxycytidine and deoxyguanosine rescued TMZ-sensitivity, suggesting an RRM2-driven mechanism of chemoresistance, established by regulating the production of these nucleotides. In vivo, tumor-bearing mice treated with the RRM2-inhibitor, Triapine, in combination with TMZ, survived longer than mice treated with TMZ alone (p<0.01), indicating promising clinical opportunities in targeting RRM2. Our data present a novel understanding of RRM2 activity, and its alteration during therapeutic stress as response to TMZ-induced DNA damage.Competing Interest StatementThe authors have declared no competing interest.