PT  - JOURNAL ARTICLE
AU  - Shreya Budhiraja
AU  - Shivani Baisiwala
AU  - Ella Perrault
AU  - Sia Cho
AU  - Khizar Nandoliya
AU  - Gabriel Dara
AU  - Andrew Zolp
AU  - Li Chen
AU  - Crismita Dmello
AU  - Cheol H. Park
AU  - Adam M Sonabend
AU  - Atique U Ahmed
TI  - ARF4-mediated Retrograde Trafficking Drives Chemoresistance in Glioblastoma
AID  - 10.1101/2021.07.18.451328
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.18.451328
4099  - http://biorxiv.org/content/early/2021/07/19/2021.07.18.451328.short
4100  - http://biorxiv.org/content/early/2021/07/19/2021.07.18.451328.full
AB  - Glioblastoma (GBM) is the most common type of adult malignant brain tumor, with a median survival of only 21 months. This is partly due to the high rate of resistance to conventional therapy, including temozolomide (TMZ), leading to recurrence rates close to 100%. It still remains unknown what drives the development of this resistance. To identify the unknown genes driving the development of this resistance, we performed a genome-wide CRISPR knockout screen comparing a DMSO-treated population with a TMZ-treated population over 14 days. We identified 4 previously unstudied genes – ARF4, PLAA, SPTLC1, and PIGK – that showed significant elevations in expression in recurrent tumors in patient datasets, along with significant survival benefits corresponding to low gene expression. Further investigation of ARF4, known to be involved in retrograde trafficking, allowed us to identify a mechanism of resistance that is mediated by increased retrograde transport of EGFR into the nucleus. Ultimately, our CRISPR-Cas9 screen has identified a promising therapeutic target, ARF4, which may drive GBM’s high resistance to chemotherapy.Competing Interest StatementThe authors have declared no competing interest.