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.