A New Approach To Overcome Chemotherapy Resistance

Scientists from King’s have successfully applied a new technology that disarms one of the most potent weapons cancer cells use to weaken the effects of chemotherapy drugs.

The Efflux Resistance Breaker (ERB), a propriety technology developed at King’s, was successfully applied to the structure of a commonly used chemotherapy drug. The study, published in the Journal of Medicinal Chemistry, found that this technology was able to limit the effectiveness of pumps inside cancer cells that push out the drug while avoiding issues related to toxicity that have plagued previous approaches. This demonstrates how ERB-driven design could overcome chemoresistance, one of the most persistent challenges in cancer therapy.  

Efflux pumps are proteins found in the cell membrane that transport unwanted or harmful substances out of a cell. While they normally protect cells, cancer cells often exploit these pumps to resist chemotherapy. Some drugs are particularly vulnerable to efflux pumps because of characteristics such as behaviour and chemical structure, meaning they are easily recognised and removed.

In the study, led by Dr Madiha Chowdhury, the researchers focused on the chemotherapy drug imatinib. Imatinib is a type of drug called a tyrosine kinase inhibitor that revolutionised treatment of chronic myeloid leukaemia (CML), a rare type of cancer that affects the bone marrow and white blood cells. However, it is particularly vulnerable to efflux pumps, and therefore chemoresistance, because it is the right size and has chemical properties that allow it to be recognised and transported by the efflux pumps P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). As a result, drug levels inside the cells fall below therapeutic targets, leading to reduced effectiveness and treatment failure in resistant cancer cells.

The researchers incorporated ERB chemical fragments into the core structure of imatinib to reduce recognition by efflux pumps. The new versions of the drug were able to stay inside the cancer cells for longer instead of being pumped out. This allowed the drug to continue working, even enabling it to be effective in cancer cells that had previously become resistant to normal imatinib.

This breakthrough is the first time ERB technology has been tested and shown to work in cancer drug discovery and opens a new pathway for developing next-generation anticancer drugs designed to evade drug resistance.

The researchers believe these findings could have wide-reaching implications. Efflux pumps like P-gp and BCRP contribute to treatment failure not only in leukaemia but across many cancers, including breast, lung, ovarian, and pancreatic tumours. The authors suggest that ERB technology could be applied broadly to redesign anticancer drugs and revive compounds that previously failed in development due to efflux-related issues.

Reference: Chowdhury MM, Pretheshan P, Chowdhury NS, et al. Design, Synthesis, and Biological Evaluation of Efflux-Resistant Imatinib Derivatives. J Med Chem. 2025. doi: 10.1021/acs.jmedchem.5c01596

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