Research ArticleCancer

Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver

Science Translational Medicine  27 Jan 2010:
Vol. 2, Issue 16, pp. 16ra7
DOI: 10.1126/scitranslmed.3000389

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Abstract

About 25% of breast cancers harbor the amplified oncogene human epidermal growth factor receptor 2 (HER2) and are dependent on HER2 kinase function, identifying HER2 as a vulnerable target for therapy. However, HER2-HER3 signaling is buffered so that it is protected against a nearly two-log inhibition of HER2 catalytic activity; this buffering is driven by the negative regulation of HER3 by Akt. We have now further characterized HER2-HER3 signaling activity and have shown that the compensatory buffering prevents apoptotic tumor cell death from occurring as a result of the combined loss of mitogen-activated protein kinase (MAPK) and Akt signaling. To overcome the cancer cells’ compensatory mechanisms, we coadministered a phosphoinositide 3-kinase–mammalian target of rapamycin inhibitor and a HER2 tyrosine kinase inhibitor (TKI). This treatment strategy proved equivocal because it induced both TKI-sensitizing and TKI-desensitizing effects and robust cross-compensation of MAPK and Akt signaling pathways. Noting that HER2-HER3 activity was completely inhibited by higher, fully inactivating doses of TKI, we then attempted to overcome the cells’ compensatory buffering with this higher dose. This treatment crippled all downstream signaling and induced tumor apoptosis. Although such high doses of TKI are toxic in vivo when given continuously, we found that intermittent doses of TKI administered to mice produced sequential cycles of tumor apoptosis and ultimately complete tumor regression in mouse models, with little toxicity. This strategy for inactivation of HER2-HER3 tumorigenic activity is proposed for clinical testing.

Footnotes

  • * Present address: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

  • Citation: D. N. Amin, N. Sergina, D. Ahuja, M. McMahon, A. Blair, D. Wang, B. Hann, K. M. Koch, K. M. Shokat, M. M. Moasser, Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver. Sci. Transl. Med. 2, 16ra7 (2010).

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