1. Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain
- Author
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Congjian Xu, Ting Guo, Bin Li, and Chao Gu
- Subjects
Aging ,endocrine system diseases ,Cell Survival ,bcl-X Protein ,Bcl-xL ,Antineoplastic Agents ,Apoptosis ,Small hairpin RNA ,resistance ,Mice ,In vivo ,copy number ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,RNA, Small Interfering ,BCL2L1 ,Ovarian Neoplasms ,Tissue microarray ,biology ,Chemistry ,Cell Biology ,Fibroblast growth factor receptor 4 ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,female genital diseases and pregnancy complications ,ovarian cancer ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Female ,Ovarian cancer ,Research Paper - Abstract
Aim Overexpression of BCL2L1 (BCL-xL) was associated with platinum resistance in ovarian cancer (OvCa). However, role of copy number (CN) gain of BCL2L1 in OvCa remains elusive. Methods In silico analyses of multiple public datasets were perform. Validation was carried out in our tissue microarray (TMA) of OvCa cases. In vitro and in vivo assays was performed to explore potential targeted compound against BCL2L1-gained OvCa. Results BCL2L1 was gained in ~60% of OvCa. BCL2L1 was differentially expressed between healthy and cancerous ovarian cases. BCL2L1 gain was not prognostic either in overall or in progression-free survival but higher BCL2L1 expression was associated with worsened survival, indicating biological distinction between CN gain and overexpression of the gene. BCL2L1 gain was associated with multi-resistance to various drug with no significant sensitivity to any single agent. Only CRISPR-mediated BCL2L1 knockout, but not shRNA could be inhibitive. Combined genetic silencing of FGFR4/NCAM and BCL2L1 with shRNA induced potent inhibition of BCL2L1-gained OvCa with durable effect. Combined inhibition of FGFR/BCL-xL was required for inhibiting BCL2L1-gained OvCa in vitro and in vivo. Only dual inhibition of FGFR/BCL-xL without platinum was tolerable in vivo. Conclusion Gain of BCL2L1 is associated with resistance to multiple anti-cancer agents in OvCa. Dual inhibition of FGFR4 and BCL-xL showed potent effect and tolerable toxicity, holding promise to further translation.
- Published
- 2021