title: Targeting integrin-linked kinase to suppress oncogenic KRAS signaling in pancreatic cancer.
abstract: Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed "non-druggable" because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven EMT and growth factor-stimulated KRAS expression. This regulatory loop, however, was not noted in KRAS mutant colorectal and lung cancer cells examined as knockdown of KRAS or ILK did not affect each other's expression, suggesting that this KRAS-ILK feedback regulation is specific for pancreatic cancer. In sum, this regulatory loop provides a strong mechanistic rationale for suppressing oncogenic KRAS signaling through targeting ILK, and this creating a potential new therapeutic strategy for pancreatic cancer.
authors.affiliation: a Institute of Biological Chemistry , Academia Sinica , Taipei , Taiwan.
authors.forename: Po-Chen
authors.initials: PC
authors.lastname: Chu
authors.affiliation: b Division of Medicinal Chemistry and Pharmacognosy , College of Pharmacy, The Ohio State University , Columbus , OH , USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: c Mayo Clinic Cancer Center , Phoenix , AZ , USA.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: a Institute of Biological Chemistry , Academia Sinica , Taipei , Taiwan.|b Division of Medicinal Chemistry and Pharmacognosy , College of Pharmacy, The Ohio State University , Columbus , OH , USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000099200:Scaffold Protein ILK; C117307:KRAS protein, human
keywords: Oncogenic KRAS; autoregulatory loop; heterogeneous nuclear ribonucleoprotein A1; integrin-linked kinase; pancreatic cancer