Abstract B1-58: Computational modeling provides new insights into KRAS mutant-specific responses to targeted therapy
| Autor: | Edward C. Stites |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Cancer Research. 75:B1-58 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Emerging data suggest different activating Ras mutants may have different biological behaviors. The most striking example may be in colon cancer, where activating KRAS mutations generally indicate a lack of benefit to treatment with cetuximab, with the activating KRAS G13D mutation an apparent exception. It is unclear why patients with KRAS G13D would respond to cetuximab; KRAS G13D shares the same general biochemical defects as the other oncogenic KRAS mutants. Here, a previously developed mathematical model of the biochemical reactions that regulate Ras signaling is used to investigate this problem. The purpose of the analysis is to determine whether known mechanisms of Ras signaling allow similar, but different, Ras mutants to respond differently to the same inhibitor, and to determine if the known biochemical properties of the G13D Ras mutant are consistent with increased sensitivity to upstream inhibition. Computational analysis of the mathematical model finds that differential response to upstream inhibition between different Ras mutants is indeed consistent with known mechanisms of Ras biology. Moreover, modeling demonstrates that the subtle biochemical differences between the responsive G13D mutant and the non-responsive G12D and G12V mutants are sufficient to explain the different responses to cetuximab. Simulations further identify differences in wild-type Ras signaling as the key difference between the mutants. The analysis suggests the elevated Km for the Ras GAP reaction on the G13D mutant is the biochemical property that most contributes to differences in wild-type Ras signaling. The identification of a single parameter that influences sensitivity to a targeted therapy is significant in that it suggests an approach to evaluate other, less common, Ras mutations for their anticipated response to cetuximab. Note: This abstract was not presented at the conference. Citation Format: Edward C. Stites. Computational modeling provides new insights into KRAS mutant-specific responses to targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-58. |
| Databáze: | OpenAIRE |
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