CS18, a lab-made compound developed at Baylor College of Medicine, restored a lung cancer drug’s effectiveness in cells that had stopped responding to it, according to research published in Science Advances. The compound targets a single regulatory switch on a protein called TopBP1, which several cancer-driving pathways depend on at once. In lung cancer cells that had grown resistant to the drug osimertinib, adding CS18 made the cells sensitive to the drug again and increased cancer cell death, the study found.
TopBP1 coordinates DNA repair and growth signaling inside cells, and it has proven difficult to target directly with drugs because it interacts with so many different partners. Weei-Chin Lin, a professor of medicine in the hematology and oncology section at Baylor College of Medicine, led the team that identified one specific interaction point on the protein, a domain called BRCT7/8, and designed CS18 to block that single switch rather than shutting down TopBP1 altogether.
Targeting a Single Switch on a Multitasking Protein
As ScienceDaily reported, blocking BRCT7/8 cuts off cancer cells from several survival mechanisms at once rather than attacking just one pathway. “Of all the biological switches on TopBP1, switch BRCT7/8 interacts with several key regulators of cancer growth,” Lin said in comments distributed through EurekAlert, the science news service run by the American Association for the Advancement of Science.
The study, published in Science Advances, reported that when CS18 binds BRCT7/8, the cancer-promoting activity of two proteins, MYC and mutant p53, decreased, along with the activity of proteins involved in DNA repair. With DNA repair weakened, the cancer cells became more likely to die.
The paper describes CS18 as a compound that enhances PARP blockade, referring to a separate class of drugs, PARP inhibitors, that already exploit weakened DNA repair to kill cancer cells selectively. PARP inhibitors tend to work best in tumors that already struggle to repair their own DNA damage, such as those carrying BRCA mutations. CS18’s effect on DNA-repair proteins suggests it could extend that same vulnerability to a wider range of tumors that don’t start out with a DNA-repair defect of their own, though that combination has so far only been tested in cells and mice, not in patients.
Reversing Resistance to Osimertinib in Lung Cancer
The most striking result involved osimertinib, a drug approved to treat non-small cell lung cancer driven by mutations in the EGFR gene. Osimertinib is approved for use at several different points in a patient’s care: after surgery to prevent recurrence, for certain unresectable stage III cancers, as an initial treatment for metastatic disease, in combination with chemotherapy, and after a patient’s cancer has already progressed on an earlier EGFR-targeted drug. Resistance can develop at any of those stages, leaving patients with fewer remaining options each time it does.
In lung cancer cells that had already stopped responding to osimertinib, adding CS18 restored their sensitivity to the drug and increased cancer cell death, Lin’s team reported. The researchers tested CS18 beyond lung cancer as well, in triple-negative breast cancer, ovarian cancer, lung squamous cell carcinoma and acute myeloid leukemia cells, with similar effects on the same tumor-promoting pathways. That breadth is part of what makes BRCT7/8 an appealing target: the same switch appears to matter across cancer types that otherwise have little in common.
Still Years From a Patient’s Bedside
The findings so far come from cell lines and animal models rather than human patients. Lin’s team reported reduced tumor growth in mouse models without major signs of toxicity, but no clinical trials of CS18 in people have started. A summary posted on Baylor College of Medicine’s research blog said the compound would need additional safety testing before it could be tried in patients whose tumors have stopped responding to standard therapy.
No dosage or timeline for a possible human trial has been announced.
Lin’s group, working with collaborators Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan and Helena Folly-Kossi at Baylor and Shwu-Jiuan Lin at Taipei Medical University, is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. The path from a compound that works in mice to one approved for patients typically runs through years of additional toxicology, dosing and manufacturing studies before a first human trial can even begin, a stretch that has stalled plenty of otherwise promising lab discoveries before they ever reached an oncology clinic.
“Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments,” Lin said, describing the problem CS18 is designed to address. Drug resistance recurs across many cancer types, and a compound able to restore sensitivity to a drug already approved for use, rather than requiring an entirely new treatment regimen from scratch, could shorten the path toward helping patients whose cancer has already been treated once and has since stopped responding.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
More from Morning Overview
- Doctors warn a silent liver disease now affects one in three American adults
- Hackers are hijacking outdated home routers, and the FBI named the models to check
- Older Teslas are wearing out in ways early owners never saw coming
- Early electric-car owners are hitting battery and screen failures no one warned them about
