The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Abstract

Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

Recent advances in understanding corticotroph pituitary tumor initiation and progression

“…Therefore, the ACTH-stimulating activity of EGF/TGF-α is elevated and may contribute to the excessive ACTH production. Indeed, comparative studies between CAs with and without mutated USP8 have already shown that the expression and activity of the EGFR are enhanced in CAs with USP8 mutations, 20, 21 although this could not be confirmed in another study 26 . In the case of SSTR5, USP8 mutations would lead to an increased expression and activity of this receptor and suggest that CAs with mutated USP8 may respond better to the treatment with pasireotide, a somatostatin analogue that suppresses CA growth and ACTH secretion through SSTR5 26, 30 .…”

“…In this context, two candidate proteins that might play a pathogenic role and be a pharmacological target in CAs with mutated USP8 have already been identified: the epidermal growth factor receptor (EGFR) 20, 21 and the somatostatin receptor type 5 (SSTR5) 26 . The tyrosine kinase receptor EGFR is expressed in corticotroph cells and mediates the ACTH-stimulating effect of the epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) 27– 29 .…”

Pituitary acromegaly: not one disease

“…Mutations in the ubiquitin-specific peptidase USP8 (Ma et al 2015, Reincke et al 2015, Hayashi et al 2016 have been identified in small tumors that were almost certainly densely granulated; these mutations may predict response to the somatostatin analog pasireotide (Hayashi et al 2016). Therefore, our ability to detect densely granulated tumors in Cushing disease, which we have experienced, may also prove to have therapeutic significance.…”

Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside

“…Patients harboring the mutations were female, had smaller adenomas, lower plasma ACTH levels, and had lower serum cortisol after 1 mg dexamethasone suppression test than did patients with Cushing disease (CD) not harboring USP8 mutations [8**]. Hayashi et al found similar characteristics in CD patients with USP8 mutations [13*]. Among 60 tumors studied, patients with mutated tumors were all female, and showed lower ACTH levels, smaller tumor size, and a higher likelihood of surgical remission compared to WT tumors.…”

“…POMC mRNA expression was higher in mutated tumors and positively correlated with USP8 mRNA expression. However, EGFR mRNA and protein expression did not differ between WT and mutant tumors, although EGFR protein expression was higher in those with aggressive Crooke’s cell adenomas [13*]. …”