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| Tyrosine kinase inhibition and cancer: The great escape
Current human epithelial growth factor receptor (HER) inhibitors are unable to induce sustained inhibition of HER3 and Akt signaling, thus limiting their anti-tumor activity. Abl-specific tyrosine kinase inhibitors (TKIs) — such as imatinib — are in clinical use to treat patients with chronic myelogenous leukemia (CML). However, this approach has not yet been applied successfully to other cancers with de-regulated tyrosine kinase activity, such as human epithelial growth factor receptor 2 (HER2)-driven breast cancer. Gefinitib, an inhibitor of the HER family, has limited clinical anti-tumor activity. In Nature, Moasser and colleagues explore why gefinitib and other HER inhibitors fail to induce tumor cell apoptosis in HER2-driven cancers.
It has previously been shown that transphosphorylation of kinase-inactive HER3 is required for downstream signaling via the phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway and that failure to inhibit this pathway underlies resistance to HER TKI therapy in vivo. Examination of the effects of continued exposure to gefitinib in HER2-overexpressing cancer cells now reveals that despite inducing sustained inhibition of epidermal growth factor receptor (EGFR) and HER2 phosphorylation, HER3 phosphorylation and Akt signaling are only transiently inhibited. Similar results were observed in gefitinib-treated mice bearing HER2-driven xenografted tumors. Moasser and colleagues show that the transient inactivation of HER3 is due to both an increase in the levels of HER3 at the plasma membrane, where HER3 phosphorylation takes place, and a decrease in the rate of receptor dephosphorylation. The authors propose that an increase in vesicular trafficking and a decrease in tyrosine phosphatase activity are likely to account for these effects. Indeed, TKIs increase reactive oxygen species, which are known to inhibit protein tyrosine phosphatases, and treatment with anti-oxidants suppresses drug-refractory HER3 signaling. The transient loss of Akt signaling also affects the degree of HER3 phosphorylation. While transfection with constitutively active Akt inhibits HER3 signaling in the presence of TKIs, inhibition of Akt signaling with a PI(3)K inhibitor leads to a compensatory increase in HER3 phosphorylation, suggesting a negative feedback loop between Akt and HER3. These results suggest that signaling inhibitors do not necessarily maintain a sustained suppressive effect on their targets, but actually interfere with an entire sequence of signaling events that can lead to a new steady-state phosphorylation level. In order to treat HER-driven cancers more effectively, the authors suggest a combinatorial treatment strategy with HER TKIs and anti-HER3 small interfering RNA, which leads to apoptotic tumor cell death — at least in vitro. Monica Hoyos Flight
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