Functional, structural, and binding studies of the atypical ER-resident protein FKBP7, a potential target in chemoresistant-prostate cancer

LUCE DRENO, SOFIAN LACOSTE, CAROLINA TIRABOSCHI, SOFIA CALPE, MARINE GARRIDO, MATTHIEU BERTRAND, ERIC JACQUET, NAIMA NHIRI, YOHANN LORIOT, KARIM FIZAZI, DANIEL COMPAGNO, NADINE ASSRIR, EWEN LESCOP*, ANNE CHAUCHEREAU*; COMPAGNO, DANIEL

Congreso; AACR Annual meeting 2022; 2022

Background: Metastatic Castration Resistant Prostate Cancer (mCRPC) is the lateststage of Prostate Cancer (PCa). Despite the use of taxane-based chemotherapies Docetaxeland Cabazitaxel, mCRPC remains lethal due to chemoresistance. We recently identifiedFKBP7 as an interesting potential therapeutic target in PCa. FKBP7 is overexpressed intaxane-resistant PCa cells and impacts both cell proliferation and Docetaxel efficacy inchemoresistant models. We also demonstrated FKBP7 affects translation and binds to thetranslation initiation complex eIF4F. FKBP7 is part of the FKBPs family, broadly expressedpeptidyl-prolyl isomerases. However, the properties of this ER-resident protein remain poorlydescribed.Methods: FKBP7 expression following chemotherapy treatment was assessed byWestern Blot and correlation between FKBP7 expression and clinical prognosis wasexamined on public cancer databases. Subcellular localization of FKBP7 was addressed bydigitonin-based fractionation. Finally, FKBP7-predicted structure was obtained with structuralmodeling servers and sequence alignments were performed on AliView. We then producedand purified the recombinant catalytic domain of FKBP7 and collected high quality 15NHSQC NMR spectra. Afterwards, we examined its interaction with well-known FKBP ligands.Results: Increased FKBP7 expression was observed upon treatment with severalcytotoxic chemotherapies in PCa-cell lines, and TCGA data underlined FKBP7 impactssurvival in other cancers than PCa. Together, this suggests an enlarged therapeutic potentialfor FKBP7 in adaptive resistance. Mechanistically, in taxane-resistant models, FKBP7overexpression did not result from higher protein stability but rather from a transcriptionalregulation. Preliminary results of subcellular fractionation showed FKBP7 is present in theER and seems to localize in the cytosol, independently of proteasomal degradation.Interestingly, we demonstrated FKBP7 N-glycosylation at position 45 and observed that theER- and cytosolic-FKBP7 apparently have distinct glycosylation states. The existence of aglycosylated-FKBP7 in the cytosol would suggest a reflux of this ER-resident protein in thecytosol to gain new functions, such as eIF4F activity regulation. At last, structural modelingpredicted a FKBP-type fold with a potential substrate specificity for FKBP7 as its catalyticpocket presents distinct composition for charge and bulkiness compared to other FKBPs.Accordingly, FKBP7 strongly binds Rapamycin and Everolimus, but surprisingly not FK506,confirming its selective binding profile.Conclusion: Our work contributes to better characterize FKBP7, an atypical ERresident FKBP, and an interesting potential target in cancer resistance. Besides, accumulationof data on its structure and specificity will help for the design of specific inhibitors.