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Adrenal (Excluding Mineralocorticoids)

MON-523 - Antitumoral Effects of Splice-Switching Oligonucleotides Targeting Insulin Receptor Alternative Splicing in Adrenocortical Carcinoma Cells

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Erika Peverelli, PhD: No financial relationships to disclose
Rosa Catalano, PhD: No financial relationships to disclose
The majority of adrenocortical carcinomas (ACC) overexpress insulin-like growth factor 2 (IGF2), which is a driving force for the neoplastic progression via the autocrine activation of its receptors insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (IR). Although previous efforts focusing on IGF1R targeting have shown limited efficacy, recent evidence highlights IR as a promising therapeutic target. Alternative splicing of exon 11 of IR generates two isoforms: IR-A, mediating mitogenic effects, and IR-B, involved in metabolic regulation. Higher IR-A than IR-B expression has been observed in ACC samples and in ACC cell lines H295R and JIL-2266 (derived from primary tumors) and TVBF-7 (derived from an ACC metastasis).
The aim of this study is to manipulate IR splicing to imbalance the ratio between the two IR isoforms favoring the metabolic one (IR-B) at expense of the mitogenic one (IR-A) and to evaluate the downstream effects of the IR splice-switching in ACC cell lines and primary ACC cultured cells. To this aim we transfected cells with splice-switching oligonucleotides (SSO) that target the CUGBP1 binding site, thereby preventing this splicing factor from promoting IR-A formation. We then measured IR-A and IR-B expression, cell proliferation, apoptosis and migration.
Our results showed that SSO transfection decreased IR-A and increased IR-B levels in all cell lines and in two ACC primary cultures.
Furthermore, consistent with the altered IR-A/IR-B ratio, cell proliferation decreased in H295R (-27.6 ± 13.3%, p< 0.05), JIL-2266 (-62.5 ± 30.5%, p< 0.05) and TVBF-7 (-43.3 ± 13.1%, p< 0.05) as well as in primary cultured cells (-35.2% and -42.3%, p< 0.01). Apoptosis also increased (+24.3 ± 13.3%, +136.2 ± 74%, +100.5 ± 91.3%, all p< 0.05 in cell lines; and +41.3%, +56.4% p< 0.01, in primary cultures, respectively). A decrease in cell migration was also observed in all cell lines (-53.5 ± 22.4%, -37.7 ± 22.6%, -64.8 ± 21.3%, all p< 0.05).
In conclusion, our results demonstrated that the SSO targeting IR exerted antitumoral effects in ACC cells, supporting a therapeutic potential of modulating IR alternative splicing as a promising strategy for the development of innovative, precision-based therapies in ACC.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*