When Cancer Drugs Get in Each Other’s Way
Dr. Nayiar Shahid - 10 August 2026
Dr. Nayiar Shahid
New targeted cancer therapies are designed to attack tumours with remarkable precision. But many drugs used to treat cancer need to enter cells to reach their therapeutic targets. That’s one of the key issues you seldom hear about. To reach their targets, these drugs must find a way through the cell membrane. That isn't always as simple as an open door.
Take for example tyrosine kinase inhibitors (TKIs). They are often combined with traditional chemotherapy drugs such as 6-mercaptopurine (6-MP) or gemcitabine. These drugs need to get into the cell to have an effect. But TKIs can bind to and block the gateways that help bring other drugs into the cell. This could pose a rather huge problem. After all, why give a drug if it is prevented from doing its job?
This question inspired our latest study in Dr. James Hammond's laboratory at the University of Alberta, recently published in PLOS ONE. We wanted to see if those TKIs were actually preventing the other drugs from entering the cell.
We started off by looking at the gateways for the other two drugs. They’re called appropriately Equilibrative Nucleoside Transporters, ENT1 and ENT2. Alongside them is another transporter, ENBT1 (Equilibrative Nucleobase Transporter), and it is responsible for bringing purine-based drugs such as 6-MP into cells.
Previous studies showed that some TKIs, including gefitinib and imatinib, could lock down the ENT1 gateway. So that meant one of the pathways was essentially out of contention. But whether they also interfered with ENT2 or ENBT1 remained a major unknown.
Our team used CRISPR-Cas9 gene editing to create human cell lines containing only ENT1, or only ENT2, or only ENBT1. By stripping away the background noise, we could test each transporter gateway in isolation.
We screened seven commonly used TKIs against these isolated transporter systems. What we found was intriguing: several TKIs did block ENBT1, with gefitinib emerging as the strongest blocker.
At first glance, this looked like potentially bad news. If gefitinib blocks the entry route used by 6-MP, would it make the chemotherapy less effective?
Surprisingly, when we tested both drugs together in K562 leukemia cells, the combination did not weaken the treatment. Instead, it made the combination more effective!
Instead of a roadblock, we discovered a synergistic interaction. How could that be?
This may happen because gefitinib affects more than just transporters. It may also influence how 6-MP is processed inside the cell, which could help explain the stronger response.
Our team also found another important detail: although TKIs can block these transporter doors, the TKIs do not rely on them to enter cells. Even when the transporters were removed, gefitinib still got into the cells and kept working, showing that it takes a different route inside.
These findings highlight an important lesson: cancer drugs do not work in isolation. They can interact with transporters, enzymes, and with one another in ways that may weaken or strengthen treatment. By understanding these interactions, researchers can design smarter combination therapies that make better use of each drug.