"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."

Targeting Cancer's Survival Network

Rather than focusing on a single cancer pathway, the researchers set out to develop a drug that could interfere with a broader control center involved in several cancer-promoting processes at once. Their target was topoisomerase IIß-binding protein 1 (TopBP1), which the team describes as a 'biological switchboard' because it helps regulate multiple pathways associated with cancer growth and survival.

The researchers wanted to determine whether disrupting this central control point could produce longer-lasting treatment responses and help 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

To find a compound capable of blocking BRCT7/8, the researchers screened thousands of chemicals with a combination of computer modeling and laboratory experiments. This search identified a compound known as 3B6.

The team then modified 3B6 and tested numerous versions of the molecule, eventually identifying CS18 as 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."

Testing CS18 Across Multiple Cancers

The researchers saw these effects across several types of cancer cells, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia. CS18 was also less toxic to non-cancerous cells.

The results became particularly notable when CS18 was paired with cancer drugs that are already in use. Combining CS18 with treatments such as PARP inhibitors or osimertinib killed cancer cells more effectively than either treatment used 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

Based on these findings, the researchers suggest that CS18 warrants further development as a possible component of combination cancer therapies. Such treatments could potentially help prevent resistance from emerging or make resistant cancers responsive to therapy again.

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).