Researchers at the Baylor College of Medicine have developed an experimental small-molecule drug known as CS18 that offers a potential new avenue for tackling tumors that have grown resistant to standard cancer therapies. Published in the journal Science Advances, the new study provides early yet compelling laboratory evidence supporting further investigation of CS18 as a cornerstone for future oncological treatments. By targeting a central regulatory hub within cancer cells rather than a single isolated pathway, the compound successfully disrupted multiple survival mechanisms simultaneously, offering renewed hope for patients facing difficult-to-treat relapses.
The challenge of drug resistance remains one of the most formidable hurdles in modern oncology. While many conventional treatments achieve notable success during the initial phases of patient care, a significant number of individuals eventually experience a relapse. This occurs because cancer is remarkably adaptable; surviving cells can activate compensatory and convergent biological pathways to bypass the toxic effects of therapy, ultimately promoting tumor survival and unchecked proliferation.
"Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments," explained corresponding author Dr. Weei-Chin Lin, professor of medicine in the sections of 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."
Targeting Cancer’s Survival Network
To address this adaptability, the research team shifted away from the conventional approach of targeting a single isolated cancer pathway. Instead, they sought to develop a therapeutic agent capable of interfering with a broader, more centralized control center that orchestrates several cancer-promoting processes at the exact same time. Their primary target was topoisomerase IIβ-binding protein 1, commonly referred to as TopBP1. The investigators describe this protein as a crucial ‘biological switchboard’ because it helps regulate multiple distinct pathways associated directly with cancer cell growth, DNA repair, and survival.
By focusing on this master control point, the team aimed to determine whether disrupting such a central node could produce deeper, longer-lasting treatment responses and systematically help overcome drug 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, who is also a dedicated 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
Finding a chemical compound capable of effectively blocking the BRCT7/8 switch required an extensive screening process. The research team evaluated thousands of distinct chemical candidates by combining advanced computer modeling techniques with rigorous laboratory experiments. This exhaustive search ultimately identified a promising baseline compound known as 3B6.
Recognizing the potential of 3B6, the team did not stop there. They systematically modified the molecule and tested numerous structural versions of it, striving to optimize its potency, stability, and therapeutic properties. Through this iterative process of chemical refinement, they identified CS18 as the most effective and viable candidate for further preclinical development.
"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 noted. "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."
Testing CS18 Across Multiple Cancers
To validate the broad utility of their new compound, the researchers tested CS18 across a diverse panel of human cancer cells representing several aggressive and difficult-to-treat malignancies. These laboratory tests included triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, and acute myeloid leukemia. Notably, the experimental compound demonstrated these cancer-killing effects while remaining comparatively less toxic to healthy, non-cancerous cells.
The research team achieved particularly remarkable results when they paired CS18 with existing, clinically approved cancer medications. Combining CS18 with established therapies such as PARP inhibitors or targeted treatments like osimertinib eradicated cancer cells significantly more effectively than either treatment administered on its own.
"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."
A Potential Strategy Against Drug Resistance
Building on these encouraging laboratory and animal model findings, the researchers suggest that CS18 warrants robust, continued development as a prospective component of novel combination cancer therapies. Such combination strategies could potentially serve a dual purpose in clinical settings: helping to prevent the emergence of therapeutic resistance in newly diagnosed patients, or making treatment-resistant cancers responsive to therapy once again after a relapse has occurred.
The study was conducted by a collaborative team at Baylor College of Medicine, including Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan, and Helena Folly-Kossi, alongside Shwu-Jiuan Lin at Taipei Medical University.
The research received substantial financial backing from the National Institutes of Health through grants R01CA203824, R01CA269971, T32CA174647, and T32GM136560, as well as from the Department of Defense via grants W81XWH-18-1-0329, W81XWH-19-1-0369, W81XWH-22-1-0226, W81XWH-22-1-0534, and HT9425-24-1-0045. Additional financial support was provided by a Rivkin Center for Ovarian Cancer Pilot Award and a grant from the Taiwan Ministry of Science and Technology under reference MOST 107-2635-B-038-001.