Research ArticleCancer

PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma

See allHide authors and affiliations

Science Translational Medicine  23 Sep 2020:
Vol. 12, Issue 562, eaay0152
DOI: 10.1126/scitranslmed.aay0152

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

A chink in cholangiocarcinoma’s armor

Cholangiocarcinoma is a bile duct cancer with limited therapeutic options and no established second-line treatment. In a screening assay looking for potential therapies to treat cholangiocarcinoma, Jiang et al. identified proteasome inhibitors, an established category of anticancer drugs. The authors also observed that a deficiency of the tumor suppressor PTEN, seen in many cancers including cholangiocarcinoma, sensitized the tumors to proteasome inhibitors. The researchers identified the mechanism underlying this interaction between PTEN and proteasome activity and assessed the therapeutic potential of proteasome inhibitors in mouse models as well as two patients with cholangiocarcinoma.

Abstract

Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF. BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.

View Full Text

Stay Connected to Science Translational Medicine