# The Protein Tyrosine Phosphatase 1B Modulates the Activation of Yes-Associated Protein and Sensitizes to Cytotoxic Chemotherapy in Preclinical Models of Cholangiocarcinoma

## TL;DR

This study shows that PTP1B reduces YAP activity in cholangiocarcinoma, making tumors more responsive to chemotherapy.

## Contribution

PTP1B overexpression enhances chemotherapy sensitivity in preclinical cholangiocarcinoma models by modulating YAP.

## Key findings

- PTP1B overexpression decreases YAP activation and tumor growth in CCA models.
- PTP1B inhibition increases YAP activity and cell proliferation in CCA cells.
- PTP1B overexpression improves the efficacy of gemcitabine/cisplatin in CCA tumors.

## Abstract

PTP1B is a YAP-interacting phosphatase that can decrease the tyrosine phosphorylation and transcriptional activity of YAP.PTP1B overexpression can decrease tumor growth in vivo and can increase sensitivity to standard of care chemotherapy in CCA.

PTP1B is a YAP-interacting phosphatase that can decrease the tyrosine phosphorylation and transcriptional activity of YAP.

PTP1B overexpression can decrease tumor growth in vivo and can increase sensitivity to standard of care chemotherapy in CCA.

Lacking effective therapeutics, cholangiocarcinoma (CCA) remains a deadly malignancy of the biliary tract. The Hippo pathway effector protein Yes-associated protein (YAP) is implicated in CCA pathogenesis and chemotherapeutic resistance; however, the oncogenic mechanisms underlying YAP regulation remain incompletely understood. An enhanced understanding of YAP and its role in CCA may uncover novel therapeutic targets and better define resistance pathways. Human CCA cells and murine syngeneic CCA models were utilized to explore the molecular relationship of YAP and protein tyrosine phosphatase 1B (PTP1B). Previous work in CCA has demonstrated that YAP interacts with multiple protein tyrosine phosphatases, including SHP2 and PTP1B. We observed that PTP1B pharmacologic inhibition was associated with increased cell proliferation and YAP target gene expression, while genetically enforced overexpression of PTP1B was associated with a decrease in YAP activation. Treatment of CCA cells in vitro and syngeneic, orthotopically implanted CCA murine tumors in vivo with standard cytotoxic chemotherapy, gemcitabine/cisplatin, had enhanced efficacy in the setting of PTP1B overexpression. These findings demonstrate that pYAPY357 can be modulated through protein tyrosine 1B phosphatase activity, and reducing pYAPY357 through enhanced phosphatase levels can sensitize CCA to chemotherapy.