Oncogenic PIK3CA mutation enhances cyclin D1-driven parathyroid tumorigenesis in transgenic mice

Parathyroid carcinoma is a rare but life-threatening malignancy. Limited treatment options are available for the more than 50% of parathyroid carcinoma patients who develop recurrent disease following surgery with curative intent. Many such patients will become refractory to medical management, eventually succumbing to the sustained, progressive hypercalcemia caused by parathyroid hormone-secreting tumors. Identification of genetic/molecular aberrations that might serve as “actionable targets” for pharmacologic intervention in parathyroid carcinoma have uncovered frequent inactivation of the CDC73 tumor suppressor gene, amplification of the cyclin D1 oncogene and activating mutations of the PI3K/MTOR pathway. We sought to combine these frequent tumor driving mutations to develop a novel preclinical model that could mimic the clinical course of recurrent/metastatic parathyroid carcinoma, for study of disease progression and to eventually develop/test novel preventative/therapeutic interventions. To this end, we crossed existing mouse models with genetic alterations known to occur in human parathyroid carcinomas, namely PTH-cyclinD1 transgenic mice (PCD), oncogenic Pik3ca mutant mice (Pik3caH1047R) and parathyroid-specific Cdc73 knockout mice. PCD mice develop biochemical hyperparathyroidism and parathyroid tumors with known kinetics. Mice harboring double and triple genetic modifications were evaluated independently and compared to PCD and wild type littermate controls. Assessment of progression of biochemical hyperparathyroidism was evaluated by monthly blood collection followed by measurement of serum calcium and parathyroid hormone (PTH). We observed that activation of Pik3ca in the absence of cyclin D1 overexpression was insufficient to drive parathyroid tumorigenesis and that loss of Cdc73 did not appear to enhance parathyroid tumorigenesis beyond the contribution of cyclin D1 overexpression. However, crossed mice harboring activating mutations of both cyclin D1 and Pik3ca developed more severe biochemical primary hyperparathyroidism than those with activated cyclin D1 alone. Some PCDxPik3caH1047R mice developed atypical histologic features consistent with aggressive parathyroid tumors. Thus, the combination of activated Pik3ca and cyclin D1 overexpression appears to yield a more aggressive parathyroid tumor phenotype. Our findings carry important potential therapeutic implications: the combination of cdk4/6 inhibitors with PI3K/MTOR inhibitors is under active investigation in other tumor types and the efficacy of such combination therapy merits investigation in parathyroid carcinomas which may harbor both cyclin D1 amplifications and activating mutations in PI3K/MTOR.