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P720R USP8 Mutation Is Associated with a Better Responsiveness to Pasireotide in ACTH-Secreting PitNETs
Donatella Treppiedi1, Giusy Marra1, Genesio Di Muro1,2
1Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
Cancers
|May 28, 2022
Summary
Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene impact pasireotide response in adrenocorticotroph hormone (ACTH)-secreting pituitary tumors. The P720R USP8 mutation may predict a favorable response to pasireotide treatment.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Somatic mutations in USP8 are linked to increased somatostatin receptor subtype 5 (SSTR5) in ACTH-secreting pituitary neuroendocrine tumors (PitNETs).
- The therapeutic potential of pasireotide, a somatostatin multi-receptor ligand, in relation to USP8 mutational status remains unexplored.
Purpose of the Study:
- To investigate the impact of USP8 mutations on the responsiveness of corticotroph tumor cells to pasireotide.
- To determine if USP8 mutational status can predict treatment outcomes for pasireotide therapy.
Main Methods:
- In vitro studies using human and murine corticotroph tumor cells.
- Transfection with USP8 mutants (S718del, C40-USP8, S718P, P720R).
- Assessment of SSTR5 expression, ACTH secretion, cyclin E levels, and protein-protein interactions (USP8-14-3-3) via in situ Proximity Ligation Assay and immunofluorescence.
Main Results:
- USP8 mutations (S718del, C40-USP8) abolished pasireotide sensitivity in vitro.
- Pasireotide failed to reduce ACTH secretion in S718P USP8-mutated cells but was effective in P720R USP8-mutated cells.
- P720R USP8 overexpression in AtT-20 cells increased SSTR5 expression and maintained pasireotide's efficacy in reducing ACTH and cyclin E, while preserving 14-3-3 binding without altering SSTR5 localization.
Conclusions:
- The P720R USP8 mutation may serve as a molecular predictor for a favorable response to pasireotide in corticotroph tumor cells.
- Specific USP8 mutations differentially affect pasireotide responsiveness, highlighting the importance of molecular profiling in treatment selection.
