Investigation of PI3K functional compensation VIA activated tyrosine kinases

Abstract

Protein tyrosine kinases and serine-threonine kinases have crucial functions in cell signaling, differentiation, motility, and proliferation. PI3K is the most deregulated pathway in human cancers and an essential regulator of cellular proliferation. PI3K pathway is activated via oncogenic Ras/receptor tyrosine kinases (RTKs), PTEN loss, or activating mutations in PI3Ks. Moreover, PI3K is one of the most promising pathways for targeted therapies. Thus, many serine-threonine or tyrosine kinases contribute to drug resistance elicited by PI3K inhibition. In order to identify an individual tyrosine kinase that contributes to PI3K functional compensation, the activated tyrosine kinase library was screened and found out that ZAP70 can compensate growth upon PI3K abrogation. This study suggests a mechanism of activated ZAP70 mediated partial resistance in MEFs lines. Moreover, we demonstrated the role of activated tyrosine kinase, ZAP70, in cancer cells as a tumorinitiating factor. Activated ZAP70 is able to enhance the growth ability of untransformed cells. Also in these cells, activated ZAP70 can develop partial resistance to PI3K inhibition. This resistance occurs via activated downstream targets of tyrosine kinase signaling such as STAT3/MAPK axis. Furthermore, we showed that activated ZAP70 has a high transformation capability associated with the formation of malignant phenotype in untransformed cells. Overall, ZAP70 may be a potent driver of proliferation and transformation in untransformed cells as well as in cancer cells.