Researchers at Baylor College of Medicine have developed an experimental anticancer compound that appears to make treatment-resistant tumors vulnerable again. Known as CS18, the drug targets a molecular control point called topoisomerase IIβ-binding protein 1, or TopBP1, and was shown to increase the effectiveness of established cancer therapies in laboratory and animal studies. The findings, published in Science Advances, suggest that blocking several survival mechanisms simultaneously could offer a new strategy against cancers that recur after initially responding to treatment.
Therapeutic resistance remains one of oncology’s most difficult challenges. Cancer cells are genetically and biologically adaptable, and treatment can select for populations that activate alternative pathways to repair damage, continue dividing or evade cell death. As a result, a therapy that produces a strong response at first may eventually lose its effect, allowing the disease to return. “Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments,” said Dr. Weei-Chin Lin, professor of medicine—hematology and oncology and of molecular and cellular biology at Baylor, who led the study.
The Baylor team focused on TopBP1 because the protein functions as a kind of molecular switchboard. Rather than controlling only one process, TopBP1 coordinates multiple pathways involved in DNA replication, DNA damage responses and cancer-cell survival. The researchers concentrated on a region known as the BRCT7/8 domain, which acts as a docking interface for other regulatory proteins. Interrupting this interface could therefore affect several cancer-promoting systems at once, potentially reducing the ability of malignant cells to compensate when one pathway is blocked.
Among the proteins that interact with TopBP1-BRCT7/8 are MIZ1, a regulator that can suppress the cancer-driving protein MYC; mutant forms of p53, which may acquire functions that actively promote tumor growth; and PLK1 and CIP2A, proteins that support cell division and help cancer cells withstand stress. These interactions give TopBP1-BRCT7/8 an unusually broad influence over tumor biology. The researchers reasoned that a compound capable of selectively disrupting the domain might weaken several lines of defense at the same time.
To find such a compound, the team combined computer-based structural modeling with laboratory screening. Thousands of chemical molecules were evaluated for their ability to fit into the BRCT7/8 binding region and interfere with its interactions. An initial hit, called 3B6, provided a chemical starting point, but it was not sufficiently effective to serve as a promising drug candidate. Researchers chemically modified the compound through multiple rounds of optimization, ultimately producing CS18, which displayed stronger activity in cellular experiments.
The experiments indicated that CS18 affects cancer cells through several connected mechanisms. When the compound binds to TopBP1-BRCT7/8, the activity of MYC and mutant p53 declines, while proteins involved in DNA repair become less effective. At the same time, genes that restrict uncontrolled cell growth become more active. This combination may leave cancer cells unable to repair treatment-induced damage or maintain the signaling programs required for survival, increasing the likelihood that they will undergo programmed cell death.
CS18 produced these effects across a range of malignant cell types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia. In the researchers’ tests, the compound was less damaging to noncancerous cells than to cancer cells, although such findings do not establish safety in humans. The broad activity was particularly important because it suggested that TopBP1 inhibition could be relevant across tumors driven by different genetic abnormalities rather than being limited to a single cancer subtype.
The most notable results emerged when CS18 was combined with existing treatments. In cancer models, the compound enhanced the activity of PARP inhibitors, drugs that prevent cells from repairing certain forms of DNA damage. Tumor cells already operating under heavy replication and repair stress may be especially dependent on the remaining repair pathways, making them vulnerable when TopBP1 signaling is also disrupted. CS18 likewise strengthened the effect of osimertinib, a targeted therapy used against certain lung cancers driven by mutant epidermal growth factor receptor, or EGFR.
The combination was particularly effective in cells that had already developed resistance to osimertinib. Adding CS18 restored their sensitivity to the EGFR inhibitor and increased cancer-cell death, indicating that TopBP1 blockade may help dismantle resistance mechanisms rather than simply adding another independent source of toxicity. In animal models, treatment combinations significantly reduced tumor growth without major weight loss or other obvious signs of toxicity during the experiments. However, the results remain preclinical, and further studies will be needed to determine how the compound is absorbed, distributed and metabolized, as well as whether its benefits outweigh potential risks in people.
The researchers describe CS18 as a candidate for further drug development, not as an available cancer treatment. Additional work will need to establish the compound’s precise pharmacology, optimal dosing, long-term safety and effectiveness in more representative tumor models. Clinical trials would ultimately be required to determine whether the strategy can help patients whose cancers resist PARP inhibitors, osimertinib or other therapies. If those studies are successful, targeting TopBP1-BRCT7/8 could lead to combination treatments designed not only to shrink tumors, but also to prevent cancer cells from activating escape routes that enable relapse.
Subject of Research: Cells
Article Title: Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib resistance
Web References: https://doi.org/10.1126/sciadv.aeg1996; https://www.bcm.edu/people-search/weei-chin-lin-25464
References: Science Advances, DOI: 10.1126/sciadv.aeg1996
Keywords
CS18, TopBP1, cancer drug resistance, cancer therapy, PARP inhibitors, osimertinib, lung cancer, triple-negative breast cancer, ovarian cancer, acute myeloid leukemia, molecular oncology, drug development
Tags: Baylor College of Medicine cancer researchcancer drug resistancecombination therapy approachesexperimental anticancer compoundslab and animal studies on cancer drugsmolecular mechanisms of cancer survivalnew strategies for resistant tumorsovercoming therapy resistance in cancerrole of TopBP1 in DNA repairscience advances cancer treatmenttargeting multiple cancer survival pathwaysTopBP1 protein targeting
