Hippo pathway mediates resistance to cytotoxic drugs.

TitleHippo pathway mediates resistance to cytotoxic drugs.
Publication TypeJournal Article
Year of Publication2017
AuthorsGujral TS, Kirschner MW
JournalProc Natl Acad Sci U S A
Volume114
Issue18
PaginationE3729-E3738
Date Published2017 May 02
ISSN1091-6490
Abstract

Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that "switching off" of the Hippo-YAP pathway could help to prevent or reverse resistance to some cancer therapies.

DOI10.1073/pnas.1703096114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28416665
PubMed Central IDPMC5422801
Grant ListR01 GM103785 / GM / NIGMS NIH HHS / United States
R01 HD073104 / HD / NICHD NIH HHS / United States