A kinase inhibitor screen identifies GSK690693 as a Hippo pathway inhibitor targeting ER-positive breast cancer.

The Hippo pathway, traditionally recognized for its tumor suppressive function, has been paradoxically implicated in promoting tumor progression in cancers, such as estrogen receptor-positive breast cancer. Treatment of ER-positive breast cancer faces notable challenges owing to the growing incidence of tumor resistance to hormonal therapies, highlighting the need for alternative therapeutic strategies. Here, we explored potential Hippo pathway inhibitors through the multistep screening of 1150 kinase inhibitors and identified GSK690693 as a potent inhibitor of the Hippo pathway, specifically targeting LATS1 kinase activity. GSK690693 effectively downregulated ER expression in MCF-7 breast cancer cells by suppressing the Hippo pathway activity. Mechanistically, treatment with GSK690693 led to cell cycle arrest and induction of cell death. These findings revealed a previously undefined mechanism of action of GSK690693 as a Hippo pathway inhibitor, underscoring its efficacy in mitigating ER-positive breast cancer progression. Given the broader implications of Hippo pathway dysregulation in multiple cancers, GSK690693 could be part of a combination regimen for various malignancies.