Hippo pathway mediates resistance to cytotoxic drugs

Significance

Cytotoxic therapy is still the backbone of effective chemotherapy, although most current pharmaceutical interest is in targeted therapy. Our findings concern a general adaptive response of cells that causes resistance to gemcitabine and 15 other FDA-approved cytotoxic drugs when cells are grown at high density. Although on the surface cell confluence seems like it could be an irrelevant property of cells in culture, our work shows that it is very relevant to tumors in mice and retrospectively to the success of chemotherapy in humans. On a fundamental cell biological level, these studies identify a previously unappreciated function of the enigmatic Hippo pathway, which controls this response. “Switching-off” this pathway could present an opportunity to overcome drug resistance in pancreatic cancer.

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.