PROJECT SUMMARY The platinum-based chemotherapy has been widely used for treating a variety of solid tumors including breast, lung and ovarian cancers. Initial therapeutic success is achieved by the platinum-based chemo-drugs like cisplatin; however, a number of tumors are found to be intrinsically resistant or gradually develop resistance to cisplatin treatment. This resistance greatly limits their therapeutic potential. Notably, the platinum-based compounds are the only heavy metal containing chemo-drugs applied to cancer treatment, which results in unique mechanisms accounting for their resistance. Of them, the cellular defensive machinery, which sequesters, stores, transports and expels heavy metals, represents a mainstay of such platinum-based drug resistance. Therefore, elucidating the regulation of heavy metal response will help not only identify key players that drives cisplatin resistance in human cancers, but also develop chemo-sensitizing approaches for the treatment of patients suffered from the cisplatin-resistant cancers. Studies from multiple model systems have fully established the Hippo pathway as a key signaling pathway that controls organ and tissue size via restricting cell proliferation and stimulating cell apoptosis. The Hippo pathway can sense growth conditions and control cell proliferation by modulating its downstream effectors YAP/TAZ. Notably, deregulation of the Hippo pathway has been connected with cisplatin resistance in human cancers, while the underlying mechanism is not fully understood. Interestingly, our preliminary studies revealed that Hippo signaling deficiency can promote the transcription of genes that are able to increase heavy metal efflux and neutralization, resulting in the cancer cell resistance to the platinum-based chemo-drugs like cisplatin. In this project, we will elucidate the role of the Hippo pathway-regulated heavy metal homeostasis in driving cisplatin resistance in Aim 1, and test whether the Hippo pathway can be employed as a chemo-sensitizer for the cisplatin- related chemotherapy in Aim 2.