title: PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1Cancer Therapeutics and Stratified Oncology, 2Information and Mathematical Science, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis; 3Graduate School for Integrative Sciences and Engineering; 4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore; and 5Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Tan
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Li
authors.forename: Puay Leng
authors.initials: PL
authors.lastname: Lee
authors.forename: Peiyong
authors.initials: P
authors.lastname: Guan
authors.forename: Mei Yee
authors.initials: MY
authors.lastname: Aau
authors.forename: Shuet Theng
authors.initials: ST
authors.lastname: Lee
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.forename: Cheryl Zihui
authors.initials: CZ
authors.lastname: Lim
authors.forename: Eric Yong Jing
authors.initials: EY
authors.lastname: Lee
authors.forename: Zhen Ning
authors.initials: ZN
authors.lastname: Wee
authors.forename: Yaw Chyn
authors.initials: YC
authors.lastname: Lim
authors.forename: R K Murthy
authors.initials: RK
authors.lastname: Karuturi
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000097869:Polo-Like Kinase 1
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1; C489427:MYC protein, human; C546842:MTOR protein, human; C578562:PDPK1 protein, human