IL-6 inhibitor may thwart HER2-targeted drug resistance

Researchers have discovered one reason why breast cancers are or become resistant to agents targeting the human epidermal growth factor receptor 2 (HER2), such as Herceptin (trastuzumab), and might have found a way to overcome this problem.

A team led by Hasan Korkaya, DVM, PhD, of the University of Michigan Medical School in Ann Arbor, found that cancer cells that are resistant to agents targeting HER2 turn on a completely different pathway that involves inflammation and the protein interleukin-6 (IL-6). This pathway fuels the cancer independently of HER2.

“There is evidence that patients with a lot of IL-6 tend to do poorly,” noted Korkaya in a statement issued by the University of Michigan Health System. “What we found now is that in many of the Herceptin-resistant breast cancers, the IL-6 inflammation loop is driving the cancer stem cell.”

Long-term trastuzumab treatment generates highly enriched cancer stem cells that secrete IL-6 in excess, leading to drug resistance. However, interrupting the inflammatory-feedback loop almost completely blocked the cancer as well as the tumor stem cells that sparked growth and metastasis of the cancer, reported the investigators in the journal Molecular Cell. Mice that were given an IL-6 receptor antibody in conjunction with Herceptin never developed resistance to Herceptin.

The IL-6 inhibitor tocilizumab (Actemra) is already FDA-approved for the treatment of rheumatoid arthritis. Korkaya and team are developing a clinical trial to test the use of this agent in conjunction with Herceptin.

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