Targeting parathyroid hormone related protein in pancreatic cancer
Parathyroid hormone-related protein (PTHrP), a secreted protein important for regulating intracellular calcium and cell proliferation, has recently been identified as having an oncogenic and pro-metastatic role in adenosquamous carcinoma of the pancreas (ASCP), an aggressive pancreatic cancer marked by atypical squamous cells. Once thought non-functional in cancer promotion, PTHrP was found to co-amplify with KRAS, a known driver oncogene, and promote tumorigenesis (Pitarresi et al., Cancer Discovery, 2021). Thus, we hypothesize that inhibiting the PTHrP signaling pathway could suppress ASCP cell proliferation. Western blotting was first used to determine the expression of PTHrP in a panel of pancreatic cancer cell lines and revealed that cell lines BxPC3 and UM59 had the highest PTHrP expression, making them optimal models for studying this pathway. To determine the effects of PTHrP inhibition, the sulforhodamine B (SRB) assay was used to measure cell growth inhibition upon the treatment of cinacalcet, a calcimimetic that inhibits parathyroid hormone secretion, alone or in combination with gemcitabine and nab-paclitaxel, the current standard of care chemotherapy drugs for metastatic pancreatic cancer. Results showed that UM59 cells demonstrated higher sensitivity to both single-agent cinacalcet and the triple-agent treatments. Furthermore, cinacalcet was more potent in inducing cell growth inhibition compared to the chemotherapeutic agents. The combination of cinacalcet and chemotherapy showed additive effects at the concentrations tested. Further investigation is needed to determine optimal drug concentrations that exhibit synergistic effects. Future studies will also investigate cinacalcet’s impact on PTHrP protein levels and downstream signaling and explore additional PTHrP inhibitors to develop an efficacious PTHrP targeted treatment for ASCP.
