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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How to Outsmart Breast Cancer

Patients with breast cancer enrolled in recent clinical trials of a drug called lapatinib had reason to be optimistic. The growth and metastasis of many breast cancers depend critically on the target of this drug, the Erb receptor human epidermal growth factor 2 (HER2), and it made sense that its inhibition would hobble the cancer’s ability to survive. But some of these patients were ultimately disappointed as only a fraction of cancers responded to the drug, and those responses tended to be partial and transient. New work by Amin et al. in human breast cancer cells tests alternative treatment strategies and suggests that one of these might outwit these cancers.

In certain breast tumors, the protein kinase activity of HER2, which is blocked by lapatinib, signals to downstream targets that cause cancer. One of these targets is another member of the same family, HER3, which can bind ligand but does not have catalytic activity of its own, and which in turn activates phosphoinositide 3-kinase (PI3K)–Akt signaling. In previous work, Amin and colleagues showed in human breast cancer cells that drug-induced altered regulation of HER3 through feedback from Akt is responsible for allowing cell to escape the lethal effects of lapatinib. Here, they probe this effect further and try to find a way to bypass the cells’ compensatory mechanism.

The first approach was to try to inhibit PI3K at the same time as HER2 tyrosine kinase, but this proved ineffective as these cells were also able to up-regulate the growth signaling pathways and bypass inhibition by this combined treatment. Next, they used much higher doses of lapatinib, which were in fact able to completely and durably extinguish HER2 activity, but which have the disadvantage of being very toxic in vivo. They found a way around this problem by giving these high doses to mice with HER2-dependent tumors on an intermittent schedule, periodically driving blood concentrations high enough to generate a wave of apoptosis in the tumor and effectively preventing growth.

The success of these authors in this skirmish with breast cancer marks a reason for renewed optimism in patients with HER2-dependent breast cancer. These second-generation approaches will need to be tested in the clinic, but the HER2-HER3 tumorigenic driver still seems to be an opponent keeping in our sites.


  • * 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).