Abstract 1653: Highly effective treatment of HER2-amplified breast cancers through the complete inactivation of the HER2-HER3 tumorigenic driver

Approximately 25% of breast cancers are driven by amplification of the HER2 oncogene and over-activity of the HER2-HER3 signaling complex. It is a promising hypothesis that the pharmacologic inactivation of HER2-HER3 signaling with tyrosine kinase inhibitors (TKIs) in patients will be a highly effective treatment for this disease. Treatment of HER2 amplified breast cancers with HER2 targeting agents shows that the HER2-HER3 complex is endowed with a two-log signal buffering capacity, making drug potency a critical and potentially limiting variable. The buffering capacity is mediated through Akt driven negative feedback signaling, which has the ability to amplify HER2-HER3 signaling and protect it against incomplete inhibition of HER2 kinase. The concomitant use of downstream inhibitors induces compound sensitizing and desensitizing mechanisms and incremental anti-tumor effects. The HER2-HER3 signal buffering mechanisms cannot ultimately compensate for the total loss of HER2 catalytic activity, and at fully inactivating doses of TKI, the failure to phosphorylate HER3 and the dual loss of MAPK and Akt pathway signaling leads to apoptotic tumor cell death. Such HER2-inactivating dosing is not tolerable in vivo using continuous schedules but is feasible and highly effective using intermittent dosing. We show that continuous dosing of the HER2 TKI, lapatinib, at its maximum tolerated dose in mice bearing HER2-amplified tumors produces modest growth inhibitory effects. However, a five day repeated intermittent schedule allows eight fold higher dosing and produces much more profound tumor regression and durable anti-tumor effects. Therefore high dose intermittent TKI therapy is an imminently testable clinical treatment hypothesis that can fully inactivate HER2-HER3 signaling by overpowering its signal buffering capacity, revealing a monotherapy potential in HER2-targeting TKIs that may surpass many of the combination therapy approaches currently being explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1653.