Experimental drug CS18 shows promise in overcoming cancer's resistance to treatment

Cancer cells are masters of escape. A tumor may shrink under chemotherapy for months, even years, before the cancer finds a way around the drug—activating backup pathways, rewiring its survival machinery, and emerging resistant to treatment that once worked. This pattern of initial response followed by relapse is one of oncology's most stubborn problems, and it's why researchers at Baylor College of Medicine set out to build a drug that doesn't just attack one cancer pathway, but disables several at once.

The drug they developed, called CS18, targets a protein called TopBP1, which functions as what the research team describes as a biological switchboard—a central hub that regulates multiple processes cancer cells depend on to grow and survive. Rather than blocking a single switch, CS18 interferes with several critical connections at once. One particular region of TopBP1, called BRCT7/8, interacts with key cancer regulators including MYC, a driver of tumor growth; mutant p53, which can acquire cancer-promoting functions; and two other proteins, PLK1 and CIP2A, that help cancer cells divide and persist. By targeting this central control point, the researchers reasoned, they might be able to produce longer-lasting treatment responses and help overcome the resistance that develops over time.

Finding CS18 required screening thousands of chemical compounds using computer modeling and laboratory testing. The initial search identified a compound called 3B6, which the team then modified repeatedly, testing numerous variations until CS18 emerged as the most potent candidate. When CS18 binds to BRCT7/8, the cancer-promoting activities of MYC and mutant p53 decrease, DNA repair proteins become less active, and cancer cells are more likely to die. At the same time, CS18 increased the activity of genes that suppress uncontrolled cancer growth—essentially flipping multiple switches in the opposite direction.

The effects appeared across several cancer types: triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, and acute myeloid leukemia. Importantly, CS18 was less toxic to healthy cells than to cancer cells, a critical distinction for any potential therapy. But the most striking results came when researchers combined CS18 with drugs already in clinical use. When paired with PARP inhibitors or osimertinib, a lung cancer drug, CS18 killed cancer cells more effectively than either treatment alone. In lung cancer cells that had already developed resistance to osimertinib, adding CS18 restored the cells' sensitivity to the drug, significantly increasing cell death. In animal models, this combination produced substantial tumor shrinkage with no major weight loss or other signs of toxicity.

Dr. Weei-Chin Lin, the corresponding author and a professor of medicine and molecular biology at Baylor, framed the challenge this way: while some cancer therapies work initially, many patients eventually relapse because cancer cells activate backup biological pathways that allow them to survive treatment. CS18 appears to address this by disabling several of those escape routes simultaneously. The researchers now argue that CS18 warrants further development as a component of combination cancer therapies—treatments that could either prevent resistance from emerging in the first place or restore sensitivity to existing drugs in cancers that have already become resistant. The work was supported by grants from the National Institutes of Health and the Department of Defense, along with funding from the Rivkin Center for Ovarian Cancer and Taiwan's Ministry of Science and Technology.