Researchers at Baylor College of Medicine have developed a drug called CS18 that disrupts the ability of cancer cells to survive therapy. The findings, published in Science Advances , support exploring the possibility of using CS18 to treat human cancer in the future.
"Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments," said corresponding author Dr. Weei-Chin Lin , professor of medicine – hematology and oncology and of molecular and cellular biology at Baylor. "While some therapies are effective at the beginning, many patients eventually relapse because cancer cells can activate compensatory and convergent biological pathways that allow them to overcome the toxic effects of therapy, promoting survival."
In the current study, the researchers' goal was to develop a drug that would target a 'biological switchboard' – topoisomerase IIß-binding protein 1 (TopBP1) – that controls several cancer-driving pathways at once and determine whether this strategy could deliver durable responses and overcome resistance.
"Of all the 'biological switches' on TopBP1, switch BRCT7/8 interacts with several key regulators of cancer growth, including MIZ1, a suppressor of cancer driver MYC; mutant p53, which can acquire cancer-promoting functions; and PLK1 and CIP2A, proteins that help cancer cells survive and divide," said Lin, a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "All together, these diverse roles position TopBP1-BRCT7/8 as a promising target for intervention."
Developing CS18
The team screened thousands of chemical compounds using computer modeling and laboratory testing to identify molecules that could bind to the BRCT7/8 switch and block its cancer-promoting activities. They found compound 3B6, which they subsequently modified and tested many versions until they found CS18, the most effective candidate.
"When CS18 binds to BRCT7/8, the cancer-promoting activities of MYC and mutant p53 decreased, proteins involved in DNA repair became less active and cancer cells were more likely to die," Lin said. "In addition, CS18 increased the activity of genes that stop uncontrolled cancer growth. Altogether, CS18 appears to reduce several of the defenses that help cancer cells survive therapy."
The researchers observed these effects in several cancer cell types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia, while the drug was less toxic to non-cancerous cells. Importantly, combining CS18 with cancer drugs currently in use such as PARP inhibitors or osimertinib killed cancer cells more effectively than either drug alone.
"In the case of lung cancer cells that were already resistant to osimertinib, adding CS18 restored the cells' sensitivity to osimertinib, increasing cancer cell death," Lin said. "We observed a significant reduction of tumor growth in animal models with no major weight loss or other signs of toxicity."
The researchers propose CS18 is a candidate for further development as a drug that could become part of combination treatments to prevent or overcome cancer drug resistance.
Other contributors to this work include Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan and Helena Folly-Kossi, all at Baylor College of Medicine. Shwu-Jiuan Lin is at Taipei Medical University.
This work was supported by the National Institutes of Health grants (R01CA203824, R01CA269971, T32CA174647 and T32GM136560) and Department of Defense grants (W81XWH-18-1-0329, W81XWH-19-1-0369, W81XWH-22-1-0226, W81XWH-22-1-0534 and HT9425-24-1-0045). Further support was provided by a Rivkin Center for Ovarian Cancer Pilot Award and a Taiwan Ministry of Science and Technology grant (MOST 107-2635-B-038-001).
