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- W2023363762 abstract "Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCRAF inhibitors have remarkable activity in melanomas harboring BRAFV600E mutations. We previously found that active Ras induces RAF dimers in tumors with wild-type RAF, and, that RAF inhibitors transactivate these dimers. Because BRAFV600E melanomas have enhanced ERK signaling, they are hypothesized to have feedback-mediated suppression of Ras in order to maintain monomeric and inhibitor-sensitive BRAFV600E. To test this hypothesis we evaluated the response of these tumors to RAF inhibitors over time. We found that in the treatment-naive state, BRAFV600E melanomas had suppressed RTK signaling and maintained a low level of Ras-GTP. This occurred through a multifactorial negative feedback process driven by active ERK. In this baseline state, BRAFV600E was sensitive to RAF inhibitors. After treatment with RAF inhibitors, however, inhibition of ERK signaling lead to loss of feedback, a process that restored signaling from RTKs and resulted in Ras activation. In turn, this diminished the effect of RAF inhibitors and lead to a partial, but sustained, reactivation of ERK signaling. In this post-treatment state, ERK signaling was insensitive to RAF inhibitors but sensitive to MEK inhibitors. Targeting the regulatory components of this new steady state, either through co-administration of a MEK inhibitor or a RTK inhibitor along with a RAF inhibitor resulted in improved antitumor activity. These results highlight the need to understand the adaptive response to ERK pathway inhibition in order to design better combinatorial therapies and achieve maximal antitumor effects.Citation Format: Piro Lito, Christine Pratilas, Eric Joseph, Madhavi Tadi, Ensar Halilovic, Matthew Zubrowski, Alan Huang, Elisa de Stanchina, Sarat Chandarlapaty, Poulikos Poulikakos, Neal Rosen. Feedback dependent suppression of mitogenic signaling and its effect on RAF inhibition in BRAFV600E melanomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4630. doi:10.1158/1538-7445.AM2013-4630" @default.
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- W2023363762 date "2013-04-15" @default.
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- W2023363762 title "Abstract 4630: Feedback dependent suppression of mitogenic signaling and its effect on RAF inhibition in BRAFV600E melanomas." @default.
- W2023363762 doi "https://doi.org/10.1158/1538-7445.am2013-4630" @default.
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