유전체 스크리닝을 이용한 교모세포종 세포주의 유전형 특이적 암 취약성과 temozolomide 내성 메커니즘 규명

Abstract

Glioblastoma (GBM) is a malignant brain tumor that accounts for 15.4% of all primary CNS tumors and brain tumors [1]. The prognosis of GBM patients is very poor and temozolomide (TMZ) chemotherapy improves the dismal prognosis of GBM [2, 3]. However, the accumulation of mutations in GBM forms inter-tumor heterogeneity and allows the acquisition of TMZ resistance in GBM making GBM therapeutic strategies more complex [4-6]. EGFRvIII is one of the most common mutations in GBM and is a sufficient condition for gliomagenesis [7-9]. Deletion of the CDKN2A gene cooperates with EGFRvIII and shortens the latency period of EGFRvIII- mediated gliomagenesis [7, 10]. CDKN2A deletion is associated with poor overall survival of GBM patients [11]. Here I showed context-specific essential genes and genotype-specific cancer vulnerabilities in the mouse EGFRvIII GBM cell line (GBMEGFRvIII) and CDKN2A KO EGFRvIII GBM cell line (GBMEGFRvIII;CDKN2A KO). For this, I developed the GBMEGFRvIII;CDKN2A KO cell line by utilizing the GBMEGFRvIII cell line from previous research [7] and conducted bulk RNA-seq and genome-wide CRISPR-Cas9 screening [12]. My research demonstrates that the transcriptional pattern of GBMEGFRvIII and GBMEGFRvIII;CDKN2A KO is distinct and lipid-associated metabolic pathways play important roles in the fitness and TMZ sensitivity of GBMEGFRvIII;CDKN2A KO. The understanding of essential genes and cancer vulnerabilities in GBMEGFRvIII and GBMEGFRvIII;CDKN2A KO is expected to be useful in investigating GBM therapeutic targets related to CDKN2A deletion and EGFRvIII and developing personalized GBM medicines.