New Strategies to Overcome Cancer Drug Resistance Emerge from Three Research Teams

Researchers have reported new strategies to overcome cancer drug resistance, targeting the tumor cells that survive treatment, the DNA repair machinery that resistant cancers rely on, and new DNA-damaging compounds. The approaches include a robotic platform that reveals shared vulnerabilities among persister cells, a small molecule called UNI418 that disables key DNA repair proteins, and a family of tri-click ligands that cut DNA through a distinct chemical mechanism.

Cancer drugs can shrink fast-growing tumors, but sometimes a few tumor cells survive. These 'persister' cells seed new tumors, forcing cancer patients into arduous cycles of testing and treatment. Persister cells are rare — as few as one in a thousand tumor cells — and they're genetically identical to the tumor, which makes them hard to find. To figure out how to beat them, researchers at UC San Francisco built a robotic system that treats thousands of mini tumors at once in the laboratory. The system revealed shared features among persister cells that could help explain why cancer comes back. The findings appear in Science Advances.

The team gathered 94 drug candidates that other laboratories had flagged as potential persister therapies and tested each at different doses on persisters from two types of lung cancer treated with standard therapies. Of the tested drugs, nine consistently weakened persister cells, suggesting that persister cells may share common vulnerabilities, even if they had emerged under different treatment conditions. 'We expected each tumor to behave as its own special case,' said a professor of Pharmaceutical Chemistry at UCSF and co-senior author. 'Instead, we found patterns that held up across many different samples, suggesting there may be underlying rules that can help predict which therapies are most likely to work.' The team plans to expand the platform to include more tumor types and treatment conditions.

In a separate effort, researchers at the Institute for Basic Science (IBS) and Chungnam University identified a small molecule called UNI418 that can disrupt cancer's DNA repair ability. Cancer cells often survive treatment by fixing the DNA damage that therapy is meant to cause, relying on homologous recombination, a DNA repair process that depends on proteins such as RAD51 and CHK1. When cancer cells were exposed to UNI418, levels of these proteins dropped significantly. The molecule activates the Cul4A ubiquitin ligase complex, a protein disposal pathway that marks specific proteins for destruction.

The team found that UNI418 interferes with inositol phosphate metabolism, lowering levels of IP6, which normally keeps Cul4A activity under control. With IP6 reduced, Cul4A works with an adaptor protein called WDR5 to target RAD51 for destruction, shutting down homologous recombination. The result resembles DNA repair deficiency, even in cancer cells that had previously regained their repair capabilities. In cell-based studies, UNI418 made cancer cells much more sensitive to PARP inhibitors, and in cells that had already become resistant to PARP inhibitor treatment, it restored their responsiveness to the drugs. In tumor xenograft experiments, UNI418 slowed tumor growth, especially when used together with the PARP inhibitor Olaparib, including in models designed to mimic treatment-resistant cancers.

A third approach comes from a European consortium including scientists from Dublin City University (DCU) and the University of Limerick (UL), along with Chimie ParisTech, Chalmers University of Technology, and Sahlgrenska University Hospital. The team developed a new chemical strategy for designing metal-based compounds capable of damaging cancer cell DNA. Using click chemistry, they created a family of compounds known as tri-click ligands, which when combined with copper ions form artificial metal-containing agents designed to cleave DNA. These molecules cut DNA through a distinct chemical mechanism compared with existing chemotherapy drugs, and the strategy could avoid some of the typical mechanisms that cancers use to become resistant. The research, published in the journal Nature, focuses on early-stage compounds that could form the basis of future therapies, particularly in cancers that become resistant to treatment.