PT  - JOURNAL ARTICLE
AU  - Jianfeng Chen
AU  - Xiaowen Ge
AU  - Wei Zhang
AU  - Peipei Ding
AU  - Yiqun Du
AU  - Qi Wang
AU  - Ling Li
AU  - Lan Fang
AU  - Yujing Sun
AU  - Pingzhao Zhang
AU  - Yuzhen Zhou
AU  - Long Zhang
AU  - Xinyue Lv
AU  - Luying Li
AU  - Xin Zhang
AU  - Qunling Zhang
AU  - Kai Xue
AU  - Hongyu Gu
AU  - Qunying Lei
AU  - Jiemin Wong
AU  - Weiguo Hu
TI  - PI3K/AKT inhibition in tumor propagating cells of DLBCL reverses R-CHOP resistance by destabilizing SOX2
AID  - 10.1101/657445
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 657445
4099  - http://biorxiv.org/content/early/2019/06/02/657445.short
4100  - http://biorxiv.org/content/early/2019/06/02/657445.full
AB  - Drug resistance is a major obstacle for the success of conventional anticancer therapy, and the development of drug resistance is at least partly attributed to tumor propagating cells (TPCs). Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen. We found that the TPC proportion was remarkably increased in resistant germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL subtypes. Elevated SOX2 was the determinant for resistance development, and SOX2 was phosphorylated by activated PI3K/AKT1 signaling, thus preventing ubiquitin-mediated SOX2 degradation. Furthermore, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT1 activation. CDK6 in the GCB subtype and FGFR1/2 in the ABC subtype were SOX2 targets in the PI3K/AKT1 pathway. Chemical inhibition of PI3K/AKT1 in both subtypes, CDK6 in the GCB subtype, and FGFR1/2 in the ABC subtype significantly enhanced the susceptibility of resistant cells to CHO treatment. More importantly, PI3K and FGFR1/2 inhibitors but not a CDK6 inhibitor effectively suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting TPCs to chemo-sensitive differentiated cells. Therefore, this pro-differentiation therapy against TPCs warrants further study in clinical trials for the treatment of resistant DLBCL.