Editors' ChoiceCancer

Addicted to Cancer

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Science Translational Medicine  14 Apr 2010:
Vol. 2, Issue 27, pp. 27ec61
DOI: 10.1126/scitranslmed.3001147

Tumor cells carry multiple mutations. Yet there are examples of targeted agents, such as imatinib in chronic myelogenous leukemia, that alone have significant antitumor activity. Often, this occurs when mutations in an oncogene render it constitutively active and the tumor becomes dependent on the pathway being targeted.

In ovarian cancer, development of targeted therapies has been a challenge because such oncogenic driver mutations have not yet been identified. To search for previously unknown critical pathways in ovarian cancer, Sheng and colleagues used an RNA interference approach to suppress the activity of every known receptor tyrosine kinase in a high-throughput screen in two ovarian cancer cell lines, looking for hits that reduce cell number through either cell death or suppression of proliferation. Both cell lines demonstrated a critical dependence on one gene, ErbB3, a member of the EGF receptor family. Unlike other receptors in the family, ErbB3 is not a kinase. However, upon binding its ligand NRG1, ErbB3 heterodimerizes with other EGF receptor family members such as ErbB1 (EGFR) and ErbB2 (Her2), undergoes phosphorylation, and recruits PI3K, activating its downstream pathway to drive proliferation of the cancer cells. Sheng and colleagues now show that in more than half of ovarian cancer cell lines, ErbB3 is phosphorylated and activated. Normally, oncogenic receptors are constitutively activated because of mutations or overexpression, but neither is the case for ErbB3. Instead, the authors show that ovarian cancer cells secrete NRG1 and activate their own ErbB3 receptors in an autocrine loop. Disrupting this loop by knocking down ErbB3 or NRG1 with small interfering RNA, or treating cells with a blocking antibody against ErbB3, inhibits proliferation of the cell lines and formation of tumors in mice. From these results, the hope is that ErbB3 may represent the long-sought-after "Achilles heel" of ovarian cancer and serve as a viable target in this deadly disease.

Q. Sheng et al., An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17, 298–310 (2010). [Abstract]

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