PI3K/AKT inhibition reverses R-CHOP resistance by destabilizing SOX2 in diffuse large B cell lymphoma.

Abstract

Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, while the remaining therapeutic options are limited. Thus, understanding the underlying mechanisms and developing therapeutic approaches are urgently needed. Methods: We generated two germinal center B cell-like (GCB) and activated B cell-like (ABC) subtype R-CHO resistant DLBCL cell lines, of which the tumor-initiating capacity was evaluated by serial-transplantation and stemness-associated features including CD34 and CD133 expression, side population and ALDH1 activity were detected by flow cytometry or immunoblotting. Expression profiles of these resistant cells were characterized by RNA sequencing. The susceptibility of resistant cells to different treatments was evaluated by in vitro CytoTox-glo assay and in tumor-bearing mice. The expression levels of SOX2, phos-AKT, CDK6 and FGFR1/2 were detected in 12 R-CHOP-resistant DLBCL clinical specimens by IHC. Results: The stem-like CSC proportion significantly increased in both resistant DLBCL subtypes. SOX2 expression level remarkably elevated in both resistant cell lines due to its phosphorylation by activated PI3K/AKT signaling, thus preventing ubiquitin-mediated degradation. Further, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT activation. CDK6 in GCB subtype and FGFR1/2 in ABC subtype were SOX2 targets, whose inhibition potently re-sensitized resistant cells to R-CHOP treatment. More importantly, addition of PI3K inhibitor to R-CHOP completely suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting CSCs to chemo-sensitive differentiated cells. Conclusions: The PI3K/AKT/SOX2 axis plays a critical role in R-CHOP resistance development and the pro-differentiation therapy against CSCs proposed in this study warrants further study in clinical trials for the treatment of resistant DLBCL.

• Authors: Jianfeng Chen, Xiaowen Ge, Wei Zhang, Peipei Ding, Yiqun Du, Qi Wang, Ling Li, Lan Fang, Yujing Sun, Pingzhao Zhang, Yuzhen Zhou, Long Zhang, Xinyue Lv, Luying Li, Xin Zhang, Qunling Zhang, Kai Xue, Hongyu Gu, Qunying Lei, Jiemin Wong, Weiguo Hu
• Journal: Theranostics (Theranostics) Vol. 10 Issue 7 Pg. 3151-3163 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32194860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• AZD4547
• Aminopyridines
• Benzamides
• Benzimidazoles
• Isoquinolines
• Neoplasm Proteins
• Piperazines
• Protein Kinase Inhibitors
• Purines
• Pyrazoles
• SOX2 protein, human
• SOXB1 Transcription Factors
• Transcription Factors
• Rituximab
• Vincristine
• abemaciclib
• duvelisib
• Doxorubicin
• Cyclophosphamide
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Prednisone

Topics

• Aminopyridines (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology, therapeutic use)
• Benzamides (pharmacology)
• Benzimidazoles (pharmacology)
• Cell Differentiation (drug effects)
• Cyclophosphamide (administration & dosage)
• Doxorubicin (administration & dosage)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Isoquinolines (pharmacology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, metabolism)
• Mice
• Mice, SCID
• Neoplasm Proteins (analysis, antagonists & inhibitors)
• Neoplastic Stem Cells (drug effects)
• Phosphatidylinositol 3-Kinases (drug effects)
• Phosphorylation
• Piperazines (pharmacology)
• Prednisone (administration & dosage)
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Purines (pharmacology)
• Pyrazoles (pharmacology)
• Rituximab (administration & dosage)
• SOXB1 Transcription Factors (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Transcription Factors (analysis)
• Ubiquitination
• Vincristine (administration & dosage)
• Xenograft Model Antitumor Assays