Makoto Sudo
Email Address
csims@nus.edu.sg
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Publication Different IVIG glycoforms affect in vitro inhibition of anti-ganglioside antibody-mediated complement deposition(Public Library of Science, 2014) Sudo M.; Yamaguchi Y.; Späth P.J.; Matsumoto-Morita K.; Ong B.K.; Shahrizaila N.; Yuki N.; MEDICINE; CANCER SCIENCE INSTITUTE OF SINGAPOREPublication Short-hairpin RNA library: Identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer(Impact Journals LLC, 2015) Sudo M.; Mori S.; Madan V.; Yang H.; Leong G.; Koeffler H.P.; TEMASEK LABORATORIES; CANCER SCIENCE INSTITUTE OF SINGAPORESomatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome-wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-?B pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short-hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC.Publication Functional genome-wide screening identifies targets and pathways sensitizing pancreatic cancer cells to dasatinib(Ivyspring International Publisher, 2018) Chien W.; Sudo M.; Ding L.-W.; Sun Q.-Y.; Wuensche P.; Lee K.L.; Hattori N.; Garg M.; Xu L.; Zheng Y.; Gery S.; Wongphayak S.; Yang H.; Baloglu E.; Shacham S.; Kauffman M.; Mori S.; Phillip Koeffler H.; CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLThis study is an unbiased genomic screen to obtain functional targets for increased effectiveness of dasatinib in pancreatic cancer. Dasatinib, a multi-targeted tyrosine kinase inhibitor, is used in clinical trials for treatment of pancreatic cancer; however, intrinsic and acquired resistance often occurs. We used a dasatinib-resistant pancreatic cancer cell line SU8686 to screen for synthetic lethality that synergizes with dasatinib using a pooled human shRNA library followed by next generation sequencing. Novel genes were identified which when silenced produced a prominent inhibitory effect with dasatinib against the pancreatic cancer cells. Several of these genes are involved in the regulation of epigenetics, as well as signaling pathways of the FOXO and hedgehog families. Small molecule inhibitors of either histone deacetylases or nuclear exporter had marked inhibitory effect with dasatinib in pancreatic cancers, suggesting their potential therapeutic effectiveness in this deadly cancer. � Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) licensePublication Identification of penfluridol as potential treatment for pancreatic cancer cells(2013) Wenwen Chien; Kian Leong Lee; Qiaoyang Sun; Peer Wuensche; Makoto Sudo; Lorenz Poellinger; Jeffrey W. Tyner; Henry Yang, H.; Phillip Koeffler; MEDICINE; CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLTyrosine kinase inhibitors (TKIs) have provided promising anti-cancer activities, but intrinsic or acquired resistance to these drugs is a major problem. To overcome this resistance, we have used microarray analysis to identify a signature of intrinsic drug resistance in human pancreatic cancer cells, and applied this gene expression profile to silico drug screening for potential drugs for pancreatic cancer therapy. The potency of dasatinib (a multiple family TKI) was assessed against a panel of 14 human pancreatic cancer cell lines. This drug is undergoing clinical trials for pancreatic cancers. Nine of fourteen pancreatic cell lines were growth inhibited by dasatinib. Three dasatinib-resistant (MiaPaCa2, Panc1, SU8686) and three -sensitive (Panc0504, Panc1005, Panc0403) pancreatic cancer cell lines were used in microarray analysis to compare the gene expression profiles. A total of 598 genes were differentially expressed in dasatinib-resistant cell lines compared to the sensitive cell lines. To discover therapeutic drugs that sensitize pancreatic cancer cells to dasatinib, we performed in silico drug screening using the Connectivity Map database (CMAP). The gene signature induced by thioridazine in CMAP showed a �glove in hand� pattern to that found in dasatinib-resistant versus -sensitive pancreatic cancer cell lines. Thioridazine belongs to the phenothiazine family including chlorpromazine, perphenazine, penfluridol, and pimethixene. Each was examined. Assays of cell proliferaton, cell cycle, and Annexin V showed that each was effective at inhibiting the cell cycle and inducing apoptosis. Penfluridol (a calcium channel inhibitor) was the most potent against both the dasatinib-resistant and -sensitive pancreatic cancer cell lines. Drug combination studies of penfluridol and either dasatinib or gemcitabine (FDA-approved for pancreatic cancer) showed synergistic enhancement of cytotoxicity. Mechanistic investigations suggested that multiple signaling pathways were suppressed by penfluridol. These studies suggest a potential novel class of drugs for treatment of pancreatic cancers.