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- W3048403932 abstract "Controversially, KRAS G13D colorectal cancer patients have been reported to benefit from treatment with the EGFR inhibitor cetuximab. That EGFR inhibitors could somehow reduce signaling through a constitutively active KRAS mutant has been taken as inconsistent with known mechanisms of RAS biology. Through a combination of computational modeling and experimentation, we recently demonstrated that EGFR inhibition results in a reduction of wild-type (HRAS and NRAS) signaling in KRAS G13D colon cancer cells, but not in colon cancer cells with the other common KRAS mutants, G12D and G12V. We demonstrated this in multiple colon cancer cell lines, and we developed the hypothesis originally from our mathematical model of oncogenic RAS signal regulation adapted to biochemical rate constants for the KRAS G13D mutant. Here, we develop and analyze an alternatively parameterized version of the computational model. Analysis of this alternative model similarly suggests that EGFR inhibition causes a greater reduction of wild-type RAS signal in KRAS G13D cancers. This further substantiates our findings, analogous to demonstration in an additional cell line or an additional mouse model. In addition to reinforcing our proposed mechanism, this work also further demonstrates the power of mechanism-based computational models of protein network biochemistry in personalized cancer medicine.Note: This abstract was not presented at the conference.Citation Format: Thomas McFall, Edward C. Stites. Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 37." @default.
- W3048403932 created "2020-08-18" @default.
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- W3048403932 date "2020-06-15" @default.
- W3048403932 modified "2023-09-26" @default.
- W3048403932 title "Abstract 37: Computational analysis of the KRAS G13D colorectal cancer response to EGFR inhibition with an alternatively parameterized model" @default.
- W3048403932 doi "https://doi.org/10.1158/1557-3265.advprecmed20-37" @default.
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