PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy

• Published in: Cancer discovery Vol. 3; no. 10; pp. 1156 - 1171
• Main Authors: Tan, Jing, Li, Zhimei, Lee, Puay Leng, Guan, Peiyong, Aau, Mei Yee, Lee, Shuet Theng, Feng, Min, Lim, Cheryl Zihui, Lee, Eric Yong Jing, Wee, Zhen Ning, Lim, Yaw Chyn, Karuturi, R K Murthy, Yu, Qiang
• Format: Journal Article
• Language: English
• Published: United States 01.10.2013
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases - genetics; 3-Phosphoinositide-Dependent Protein Kinases - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival - genetics; Cell Transformation, Neoplastic; Colorectal Neoplasms - drug therapy; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplastic Stem Cells - physiology; Phosphorylation; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-12-0595

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 PDK1/PLK1 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 findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance. This work identifies 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 findings provide important insights into cancer and CSC biology and have significant therapeutic implications.