PDK1 Signaling Toward PLK1-MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy

J. Tan, Z. Li, P. L. Lee, P. Guan, M. Y. Aau, S. T. Lee, M. Feng, C. Z. Lim, E. Y. J. Lee, Z. N. Wee, Y. C. Lim, R. K. M. Karuturi (+1 others)
2013 Cancer Discovery  
Although 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of
more » ... LK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1-PLK1-MYC signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These fi ndings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance. SIGNIFICANCE: This work identifi es PDK1-PLK1-MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our fi ndings provide important insights into cancer and CSC biology and have signifi cant therapeutic implications. Cancer Discov; 3(10); 1156-71.
doi:10.1158/2159-8290.cd-12-0595 pmid:23887393 fatcat:ihfvklusajcsvkmt3z7ds4robm