What is it about?

Anticancer drugs, such as trastuzumab (Herceptin) or lapatinib (Tykerb), which act on HER2, a protein driving the growth of about one quarter of all breast cancers, show great benefit in early-stage patients. However, when these drugs are used to treat HER2-positive cancers that have already spread through the body, their benefit is often just temporary, as the tumors stop responding and become resistant to these drugs. We have shown that this problem can be alleviated by combining HER2-targeting drugs with Senexin B or SNX631, selective inhibitors of CDK8/19 Mediator kinase, an enzyme used by tumor cells to change their program of gene expression and to adapt to different therapies. Mediator kinase inhibitors prevented drug-sensitive tumors from becoming drug-resistant and overcame drug resistance that had already developed, both in cell culture and in animals.

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Why is it important?

Cancer drug resistance is the biggest overall challenge to curing cancer patients, impeding all the therapies. Our findings show that this problem can be alleviated using CDK8/19 Mediator kinase inhibitors, a new class of drugs undergoing clinical trials, by suppressing CDK8/19-driven reprogramming that allows tumor cells to adapt and survive drug treatment.

Perspectives

My colleagues and I have been struggling with the challenge of cancer drug resistance for a great number of years. Now I feel that Mediator kinase inhibitors may finally provide a way to bypass this problem for many different cancers. I feel especially gratified with the results that we obtained with HER2-positive breast cancer, a disease that has impacted someone in my own family.

Eugenia Broude
University of South Carolina

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This page is a summary of: Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2201073119.
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