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Ras mutations in the Erk-MAPK pathway and Cancer: Alternate therapies examined in an ODE-based computational model

Published: 04 December 2020 Publication History

Abstract

Oncogenic mutations in Ras GTPases result in overactivation of the Erk-MAPK pathway, which regulate cellular proliferation, and have been shown to have strong clinical correlations with a variety of pancreatic, colonic, and other cancers. To date, a viable inhibitor of Ras has remained elusive and most Ras mutation cancers are treated with downstream inhibitors to reduce the activity of ERK. However, these therapies have been shown to provide minor anticancer effects in some patients. To examine other viable therapeutic alternatives, potential drug actions that activate "off" mechanisms of this pathway are examined in a computational model. The described model recapitulates empirical data of the Erk-MAPK pathway under EGF-stimulation and is modified to include the effects of a constitutively active Ras. Serving as an experimental predictor of the potential drug actions against the effects of constant Ras activation, activators of protein phosphatase 2 (PP2A) and Raf1 phosphatase catalytic activity are shown to be able to restore Erk responses in such cancers to dynamic responses that are seen in wild-type EGF-stimulated cells.

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      ISAIMS '20: Proceedings of the 1st International Symposium on Artificial Intelligence in Medical Sciences
      September 2020
      313 pages
      ISBN:9781450388603
      DOI:10.1145/3429889
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      Published: 04 December 2020

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      Author Tags

      1. Cancer
      2. Erk-MAPK
      3. ODE-based computational model
      4. Ras mutations

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