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Bioinformatic analysis linking genomic defects to chemosensitivity and mechanism of action

  1. Author:
    Covell,David

  2. Author Address

    Natl Canc Inst, Dev Therapeut Program, Informat Technol Branch, Frederick, MD USA.
    1. Year: 2021
    2. Date: Apr 28
    3. Epub Date: 2021 04 28
  2. Journal: PloS one
  3. PUBLIC LIBRARY SCIENCE,
    1. 16
    2. 4
  5. Type of Article: Article
  6. Article Number: e0243336
  7. ISSN: 1932-6203
  1. Abstract:

    A joint analysis of the NCI60 small molecule screening data, their genetically defective genes, and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-Organizing-Maps (SOMs) are used to organize the chemosensitivity data. Student's t-tests are used to identify SOM clusters with enhanced chemosensitivity for tumor cell lines with versus without genetically defective genes. Fisher's exact and chi-square tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. These results find exploitable instances of enhanced chemosensitivity of compound MOA's for selected defective genes. Collectively these findings will advance the interpretation of pre-clinical screening data as well as contribute towards the goals of cancer drug discovery, development decision making, and explanation of drug mechanisms.

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External Sources

  1. View Full Text
  2. DOI: 10.1371/journal.pone.0243336
  3. PMID: 33909629
  4. View record in Web of Science®
  5. WOS: 000662174400003

Library Notes

  1. Fiscal Year: FY2020-2021
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