PI3K/AKT inhibition in tumor propagating cells of DLBCL reverses R-CHOP resistance by destabilizing SOX2

Chen, J.; Ge, X.; Zhang, W.; Ding, P.; Du, Y.; Wang, Q.; Li, L.; Fang, L.; Sun, Y.; Zhang, P.; Zhou, Y.; Zhang, L.; Lv, X.; Zhang, X.; Zhang, Q.; Xue, K.; Gu, H.; Lei, Q.; Wong, J.; Hu, W.

doi:10.1101/657445

bioRxiv · 10.1101/657445

PI3K/AKT inhibition in tumor propagating cells of DLBCL reverses R-CHOP resistance by destabilizing SOX2

Chen, J.·Ge, X.·Zhang, W.·Ding, P.·Du, Y.·Wang, Q.·Li, L.·Fang, L.·Sun, Y.·Zhang, P.·Zhou, Y.·Zhang, L.·Lv, X.·Zhang, X.·Zhang, Q.·Xue, K.·Gu, H.·Lei, Q.·Wong, J.·Hu, W.

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Abstract

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.

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Chen, J., Ge, X., Zhang, W., Ding, P., Du, Y., Wang, Q., Li, L., Fang, L., Sun, Y., Zhang, P., Zhou, Y., Zhang, L., Lv, X., Zhang, X., Zhang, Q., Xue, K., Gu, H., Lei, Q., Wong, J., Hu, W.. 2019-06-02. PI3K/AKT inhibition in tumor propagating cells of DLBCL reverses R-CHOP resistance by destabilizing SOX2. https://doi.org/10.1101/657445

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