title: A combination therapy for KRAS-mutant lung cancer by targeting synthetic lethal partners of mutant KRAS.
abstract: The KRAS gene is frequently mutated in multiple cancer types, but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties. As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications, we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs; we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice. An increase in the expression of the tumor suppressor P21WAF1/CIP1contributed to the synergistic mechanism of the combination therapy. These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, P. R. China. xfpang@bio.ecnu.edu.cn.
authors: Xiufeng
authors: 0000-0002-4271-8710
authors: X
authors: Pang
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, P. R. China. mliu@ibt.tamhsc.edu.|Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, 2121W. Holcombe Blvd., Houston, TX, 77030, USA. mliu@ibt.tamhsc.edu.
authors: Mingyao
authors: M
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D054460:rho-Associated Kinases; D000097869:Polo-Like Kinase 1; C493956:CDKN1A protein, human; C117307:KRAS protein, human
keywords: Combination therapy; KRAS; Polo-like kinase 1; RhoA/Rho kinase; Synthetic lethality