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news.Researchers have discovered that Roche and Genentech's Herceptin used in combination with certain cancer chemotherapies effectively treats breast cancer tumors that produce low or undetectable amounts of the HER-2 oncogene but overexpress the growth factor heregulin.
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Until now it was believed that Herceptin (trastuzumab) combined with cytotoxic drug therapy was effective only in HER-2-positive, or HER-2-overexpressing, breast cancer – which represents about 25% of all breast cancers.
In their study colleagues from the Evanston Northwestern Healthcare Research Institute found that HER-2 must be activated to exert its malignant effects. HER-2 is capable of being activated by either overexpression (overproduction) or transactivation – when a protein at one location is activated by the presence of a particular protein at another location.
Heregulin (HRG) is an activator of the HER-2 oncogene, promoting breast cancer growth and tumor formation in laboratory models. The researchers discovered that continuous production of HRG in breast cancer cells that do not overexpress HER-2 causes the receptor to be continuously activated and therefore constantly signals breast cancer cells to grow and proliferate.
Previous clinical studies have shown that trastuzumab used in combination with such cancer chemotherapy drugs as cisplatin, paclitaxel, docetaxel, vinorelbine and cyclophosphamide in HER-2-positive breast tumors is more beneficial than the antibody used alone. This effect, termed receptor-enhanced chemosensitivity (REC), was thought to target only HER-2-overexpressing cells but seemingly had no impact on cells expressing low amounts of HER-2 protein.
In the current study, the researchers used breast cancer cells genetically engineered to produce HRG to determine if HRG-induced activation of HER-2 can cause the same biologic responses as HER-2 overexpression with regards to sensitivity to chemotherapeutic drugs, such as cisplatin and paclitaxel.
They found that overexpression of HRG promotes resistance to cisplatin-induced cell death, while co-treatment of the genetically engineered cells with trastuzumab or cisplatin produced a synergistic apoptotic (cell-killing) effect. They also found that this synergy occurred with trastuzumab and either paclitaxel or vincristine.
Results of their study also support the view that trastuzumab blocks the effect of HER-2-driven activation of anti-apoptotic and proliferative cascades in breast cancer cells exhibiting HRG-dependent-activation of HER-2. Conversely, in the absence of HRG, trastuzumab promotes this effect in cells producing low amounts of the HER-2 protein.