New lab study reveals how breast cancer drug can accelerate cancer cell growth

               The breast cancer drug lapatinib which is designed to shrink tumours can sometimes cause them to grow in the lab, according to a new study published in eLife. By understanding the molecular basis of this phenomenon, scientists hope that their findings will lead to safer treatment decision-making and drug design in the future.
Lapatinib is used in combination with other cancer drugs and chemotherapy to treat patients with a particular type of advanced breast cancer, but failed clinical trials as a stand-alone treatment.
            Researchers at the Francis Crick Institute, King's College London and Barts Cancer Institute, Queen Mary University of London, have shown that lapatinib itself can actually cause breast cancer cells to grow more rapidly in some situations, which might explain the disappointing outcome of the clinical trials.
Lead author of the paper, Dr Jeroen Claus from the Francis Crick Institute, said: "If certain breast cancer drugs can cause cancer cells to grow more rapidly in particular circumstances in the lab, we need to evaluate carefully if that might happen in subsets of patients as well. Determining these risk factors could help doctors decide which patients may benefit most from these drugs."
              Around 20% of breast cancers are caused by a massive excess of a protein called HER2 (human epidermal growth factor receptor 2), which sends signals telling cancer cells to grow and divide. Lots of treatments for HER2 positive breast cancer work by switching off HER2 to make the cells stop growing or die. They can do this from outside the cell (antibodies such as trastuzumab) or inside the cell (kinase inhibitors such as lapatinib). Lapatanib is one of many kinase inhibitors used to treat HER2 positive breast cancers and HER2 is an important target for other existing and emerging breast cancer treatments.
            Using a combination of biochemical, biophysical, and computer modelling tools, the team discovered that lapatinib causes HER2 receptors on cell membranes to pair up with a partner receptor called HER3. When you combine these inhibitor-induced HER2-HER3 pairs with naturally-occurring growth signals from outside of the cell, they can rearrange themselves into an active, signalling pair. In this state, the HER2-HER3 pair becomes very efficient at telling the cells to divide, more so than cells that haven't been treated with the drug.
Professor Peter Parker, joint senior author of the paper and Group Leader at the Francis Crick Institute and King's College London (KCL) said: "Although our study was in breast cancer cells, it gives us new insights into the nuts and bolts of what happens to HER2 when you try to block it and raises some interesting questions around how we should approach designing drugs against HER2 positive breast cancer in the future."
           Professor Tony Ng, a clinician scientist heading the School of Cancer and Pharmaceutical Sciences at KCL, and joint senior author of the paper said: "In recent patient studies, HER2 targeted therapies that combined lapatinib with the antibody treatment trastuzumab successfully controlled HER2 positive breast cancers at first, but did not improve longer term disease-free survival. Our new findings could help us design future studies to improve combined HER2 targeted therapies."
Dr Justine Alford from Cancer Research UK, said: "By revealing surprising insight into the biology of HER2 and how this molecule may respond to certain drugs, this important lab research could guide future work into sophisticated new treatments that target HER2 in a more effective way.
           "As many breast cancers are triggered by HER2, drugs blocking its action have become cornerstone treatments for these diseases and they've shown great success. But sometimes these treatments can stop working, so there is a pressing need to develop new drugs that can overcome this issue and help improve the outlook for these women."
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Scientists at the University of Delaware and the University of Illinois at Chicago have found a new way to kill liver cancer cells and inhibit tumor growth. First, they silence a key cellular enzyme, and then they add a powerful drug. They describe their methods in a new paper published in Nature Communications.
          This research could accelerate the development of new treatments for liver cancer, which is currently difficult to cure. Often surgery is not an option for liver cancer, and the available drugs are only modestly effective. More than 82 percent of liver cancer patients die within five years of diagnosis, according to the National Institutes of Health.
Manipulating cells to kill cancerThis project originated in labs at the University of Illinois at Chicago, where researchers grew liver cancer cells and manipulated their expression of an enzyme called hexokinase-2. Then, the cells were treated with metformin, a diabetes drug that decreases glucose production in the liver.
         The research group of Maciek R. Antoniewicz, Centennial Professor of Chemical and Biomolecular Engineering at the University of Delaware, designed a set of experiments to measure how cancer cells respond to the loss of hexokinase-2, an enzyme that helps cells metabolize glucose, their food source.
Antoniewicz is an expert in metabolic flux analysis, a technique for studying metabolism in biological systems. His research group is one of only a few in the world with expertise in a technique called 13C metabolic flux analysis of cancer cells, and he recently published a paper in Experimental & Molecular Medicine describing his methods.
"The complexities of mammalian metabolism require a systems-level analysis of the underlying networks and phenotypes, and this is what my lab specializes in," he said.
The UD cohort used mass spectrometry to analyze the cancer cells and then determined intracellular metabolic fluxes for cells with and without hexokinase-2. They suspected that cells deprived of hexokinase-2 would starve and die, but surprisingly, they found that targeting hexokinase-2 alone had only a marginal impact on stopping cancer cell growth. Another weapon, metformin, was needed to complete the job.
           "The importance of our paper is that we show that targeting hexokinase-2 can indeed be a successful strategy for cancer therapy, when you also target a second compensatory mechanism with the drug metformin," said Antoniewicz.
His work provided important clues to what this second target should be, providing fertile ground for the next phase of research.
Finally, the research team at the University of Illinois at Chicago tested a combination of hexokinase-2 depletion and sorafenib, a liver cancer drug, on liver cancer tumors in mice. This combo worked better than either treatment alone.
The work was supported by three grants from the National Institutes of Health and a Veterans Administration merit award.