HER2 Support Group Forums - progress in discovering why herceptin doesn't work for everyone, how to supplement it

# Drug Breakthrough Could Improve Breast Cancer Survival Rates
[Breakthrough Breast Cancer]

Breakthrough Breast Cancer scientists have identified a new class of drug which could help Herceptin (trastuzumab) work much more effectively and may improve survival rates for women with an aggressive form of breast cancer.

This followed the discovery of the reason why Herceptin stops working in some breast cancer patients - representing a major leap forward in our understanding of this targeted therapy. The findings are published online in the journal PLoS Biology.

The Breakthrough Breast Cancer-funded team at the University of Oxford showed that combining Herceptin with pan-HER inhibitors kills cancer cells much more effectively than Herceptin on its own. The drug combination does this by knocking out the activity of HER2 and, crucially, its related proteins, too. These results were then confirmed in mouse models.

Dr Anthony Kong, the Breakthrough Breast Cancer clinician scientist who led the study, said: "It was incredible to see how much more potent Herceptin becomes when combined with a new type of drug. We think this could have a big impact in improving survival rates for patients with HER2 positive breast cancer.

"We are hoping to set up a clinical trial in the near future to test this treatment combination in patients."

Herceptin is currently used in combination with chemotherapy to treat HER2 positive breast cancer. Around 9,000 women are diagnosed with this type of the disease in the UK each year. While Herceptin works well for some patients, for others it either doesn't work or stops working over time. Survival rates for patients with HER2 positive breast cancer remain lower than for breast cancer overall.

The scientists discovered a key mechanism through which cancer cells develop resistance to Herceptin. They also confirmed earlier studies which showed that in some cases Herceptin is not hugely effective in killing cancer cells - it mostly delays their growth. They found that, counter to previous thinking, Herceptin does not decrease the activity of its target, the HER2 protein, and went on to find the reason behind this.

Dr Norman Freshney, Director of Research at Breakthrough Breast Cancer, said: "Since Herceptin became available, thousands of patients have benefited from this new way of targeting breast cancer. However, poor response or resistance to this drug remains a considerable problem for many patients and these results explain why this may happen.

"This work highlights the importance of understanding the biology of breast cancer and developing new ways of targeting the tumour's defects to have maximum lifesaving impact."

In recent years the work of Dr Anthony Kong has been significantly funded by a range of trusts including Mary Kinross Charitable Trust, The Holbeck Charitable Trust, Doris Field Charitable Trust and in part by The Tolkien Trust.

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OPEN ACCESS article on pLOS: HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in Response to Anti-HER2 Herceptin in Breast Cancer
[Public Library of Science: Biology]

Herceptin (trastuzumab) is used in patients with breast cancer who have HER2 (ErbB2)-positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET) methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining HER2 phosphorylation during Herceptin treatment. The activation of other HER receptors via ADAM17 may mediate acquired resistance to Herceptin in HER2-overexpressing breast cancer. This finding offers treatment opportunities for overcoming resistance in these patients. We propose that Herceptin should be combined with a panHER inhibitor or an ADAM inhibitor to overcome the acquired drug resistance for patients with HER2-positive breast cancer. Our results may also have implications for resistance to other therapies targeting HER receptors.