The intrinsic heterogeneity of endocrine-related cancers (ERCs) hampers the identification and development of global and effective therapeutic treatments for these pathologies. However, the dysregulation of the splicing process has been postulated as a new common hallmark shared by most cancer types, since it is associated with the appearance of splicing variants with oncogenic potential (e.g. CD44v6, BCL-Xs, AR-v7, SST5TMD4, In1-ghrelin). Yet, the putative alteration, pathophysiological role and potential therapeutic utility of the elements involved in the control of the splicing process [i.e. spliceosome components (SCs) and splicing factors (SFs)] remain still unknown. For this reason, we have analysed the expression levels of a representative set of SCs (n=18) and SFs (n=27) in different cohorts of ERCs [i.e. growth hormone secreting pituitary tumors (n=96); non-functioning pituitary tumors (n=23); pancreatic neuroendocrine tumors (n=20); prostate cancer (n=126); and in four in silico cohorts of liver cancer (HCC; n=445, n=115, n=75, n=45)]. Our results showed that the SF3b subunit 1 (SF3B1) gene, which encodes a protein necessary for spliceosome assembly, was consistently overexpressed in all the ERCs evaluated in this study. Interestingly, SF3B1 expression was positively correlated and associated with clinical and molecular aggressiveness features (e.g. histopathological grade, presence of metastasis, expression of oncogenic splicing variants, etc.) in these ERCs. In vitro analyses revealed that the specific blockade of SF3B1 activity, using the pladienolide-B compound, exhibited potent and relevant antitumor effects (reducing cell proliferation, migration, tumorospheres and colonies formation, hormone release and inducing apoptosis) in the vast majority of representative models of ERC cells tested herein (primary ERCs cell cultures and cell lines such as BON-1, QGP-1, LNCaP, 22Rv1, PC-3, HepG2, Hep3b or SNU-387). Remarkably, the antitumor effects of pladienolide-B treatment were further validated in vivo in that we found a significant reduction of tumor volume after 9-days of local treatment of pladienolide-B in a xenograft model of ERC. Moreover, we found that pladienolide-B treatment modulated an ample repertoire of molecular events, such as inhibition of major oncogenic signalling pathways (e.g. PI3K/AKT and JNK), modulation of the expression of key tumour markers (e.g. MKI67/CDK6/CDKN2A) and oncogenic splicing variants (e.g. AR-v7/In1-ghrelin), and regulation of the expression pattern of key components of mRNA homeostasis-associated machineries (spliceosome and SURF/EJC). In conclusion, these results indicate that SF3B1 is consistently overexpressed in different ERCs and associated to malignant features and that its pharmacological blockade with pladienolide-B could represent a novel, global and effective therapeutic approach for ERCs.
18 - 21 May 2019
European Society of Endocrinology