Editors' ChoiceCancer

Two Pluses Make a Minus

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Science Translational Medicine  01 Dec 2010:
Vol. 2, Issue 60, pp. 60ec188
DOI: 10.1126/scitranslmed.3001968

Combination therapy is both the blessing and the curse of modern medicine. In many cases, particularly in antibacterial therapy and oncology, combining agents achieves beneficial effects not observed when each individual drug is administered alone. On the other hand, patients are taking increasing numbers of unrelated medications, known as polypharmacy. Concurrently administered medications can interact with each other in sometimes unpredictable ways, enhancing or diminishing each other’s effectiveness through poorly defined mechanisms.

Liang and colleagues provide a striking example of such an interaction. They studied the effect of two biologic therapies on breast cancer cells: trastuzumab and erythropoietin. Both are in widespread clinical use in breast cancer patients, but for different reasons: Trastuzumab, a HER2 antibody, is an anticancer agent in HER2-positive patients, and erythropoietin, a recombinantly produced ligand for erythropoietin receptor (EpoR), is a red cell booster in patients with anemia. Recently, EpoR was shown to be expressed not only on red cell precursors but also on tumor cells. Because EpoR and HER2 signal through overlapping intracellular pathways, the authors hypothesized that administration of erythropoietin may diminish anticancer activity of trastuzumab by stimulating the same pathways that trastuzumab is trying to inhibit.

They found that over 80% of breast cancer samples (either HER2-positive or -negative) indeed express EpoR. To study the combination therapy in vitro, they identified breast cancer cell lines that express both HER2 and EpoR. As predicted, erythropoietin alone stimulated the proliferation of double-positive cells and diminished the inhibitory effect of trastuzumab. In contrast, when the cell lines were injected into immunodeficient mice and formed tumors, erythropoietin did not increase the growth of tumors when given alone, which is a comforting finding for an agent widely used in the clinic. However, erythropoietin diminished the antitumor activity of trastuzumab when the two drugs were combined. The authors elucidated a mechanism for this antagonism that is based on shared downstream pathways for the two receptors. They also performed a retrospective analysis of over 1900 breast cancer patients treated with herceptin at their institution, evaluating whether those patients who received erythropoietin had a different outcome from those who did not. The authors took care to minimize biases inherent in such retrospective analyses. They found that overall survival was lower in patients who received erythropoietin, but it remains a possibility that that other differences between patients who received erythropoietin and those who did not may partially account for this finding.

Although detrimental effects of erythropoietin have been observed in some clinical settings, this study demonstrates for the first time that this may be in part due to antagonism with trastuzumab. In the accompanying Editorial, Bernd Groner and Nancy Hynes stop short of recommending that the concurrent use of erythropoietin and trastuzumab be avoided. However, this study illustrates that understanding drug-drug interactions is no less important than studying individual agents, which are rarely used in isolation in patients.

K. Liang et al., Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18, 423–435 (2010). [Full Text]

B. Groner, N. E. Hynes, Unfavorable drug interactions in targeted breast cancer therapy. Cancer Cell 18, 401–402 (2010). [Abstract]

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