Abstract 3043: Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 8_Supplement; p. 3043
• Main Authors: Amin, Dhara N., Ahuja, Deepika, Ducker, Gregory S., Yaswen, Paul, Shokat, Kevan, Moasser, Mark
• Format: Journal Article
• Language: English
• Published: 15.04.2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-3043

Abstract HER2 amplified breast cancers are characterized by constitutive HER3 phosphorylation. Efforts to target the functionally relevant HER2-HER3 signaling complex in these tumor cells has proven difficult due to robust feedback signaling mechanisms that restore its signaling in the face of anything short of the complete inactivation of HER2 kinase activity. To study this in more depth, we used a combination of genetic and chemical genetic approaches designed to study the cellular adaptational responses to network perturbation. We find that positive or negative perturbation of any signaling node from upstream HER2 or HER3 down to the two mTor complexes results in compensatory responses that function to maintain homeostasis. The responses to various perturbations are mechanistically distinct, but taken together reveal an uncompromising core topology driven by a concentric Akt-mTorc2 positive-feedback loop buffered by HER3 and PHLPP nodes. While mTorc1 signaling is also subject to feedback regulation, it is not involved in the core topology and its output is not always protected in these tumors. The central role of mTor is consistent with its known functions as a master regulator of cellular homeostasis highly conserved across eukaryotes. But the inclusion of HER3 in this central homeostatic network is a tumor cell anomaly. To better delineate how this homeostatic network is altered in tumor cells, we compared and contrasted the network topology in a panel of HER2-amplified cancer cells with a panel of immortalized breast epithelial cells. Much of the feedback circuitries are preserved across tumor and untransformed cells. But the driving Akt-mTorc2 positive-feedback loop is lacking in untransformed cells. This is due to the fact that Akt drives mTorc2 signaling in tumor cells but not in untransformed cells. Consistent with a central role of mTorc2 in these tumors, knockdown of Rictor, but not Raptor, is lethal in HER2-amplified SkBr3 tumor cells. These studies reveal a key alteration of Akt-mTor signaling in HER2 driven tumors that underlies the pathological incorporation of HER3 into an mTor-driven network, thus putting the HER2-HER3 tumor driver under the protection of this evolutionarily ancient pathway, highly competent at homeostasis. Citation Format: Dhara N. Amin, Deepika Ahuja, Gregory S. Ducker, Paul Yaswen, Kevan Shokat, Mark Moasser. Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers. [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 3043. doi:10.1158/1538-7445.AM2013-3043