New experimental drug shows promise in overcoming cancer's resistance to treatment
Baylor College of Medicine researchers have developed an experimental compound called CS18 that restored cancer cells' sensitivity to existing treatments in laboratory studies. The findings were published in Science Advances.
Researchers at Baylor College of Medicine have developed an experimental compound named CS18 that may help cancer treatments regain effectiveness against tumors that have become resistant to therapy. The findings were published in the journal Science Advances.
According to corresponding author Dr. Weei-Chin Lin, a common challenge in cancer treatment is that while therapies often work initially, many patients eventually relapse because cancer cells activate additional biological pathways that let them survive despite treatment.
Targeting a biological 'switchboard'
Instead of focusing on a single cancer pathway, the researchers targeted a protein called topoisomerase IIß-binding protein 1 (TopBP1), which helps regulate multiple cancer-related processes at once. One region of this protein, known as BRCT7/8, interacts with several factors involved in cancer growth, including MIZ1 (a suppressor of the cancer driver MYC), mutant p53, and proteins PLK1 and CIP2A that help cancer cells survive and divide.
From thousands of compounds to CS18
To find a molecule capable of blocking BRCT7/8, the team screened thousands of chemicals using computer modeling combined with laboratory experiments, identifying a compound called 3B6. After modifying and testing numerous versions of this molecule, the researchers arrived at CS18 as the most effective candidate.
According to Lin, when CS18 binds to BRCT7/8, it reduces the cancer-promoting activity of MYC and mutant p53, weakens DNA repair processes, and increases the likelihood of cancer cell death, while also activating genes that suppress uncontrolled cell growth.
Tested across multiple cancer types
These effects were observed across several cancer types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, and acute myeloid leukemia. CS18 was also less toxic to healthy cells.
Results were especially notable when CS18 was combined with cancer drugs already in clinical use, such as PARP inhibitors and osimertinib — the combination killed cancer cells more effectively than either treatment alone. In lung cancer cells that had become resistant to osimertinib, adding CS18 restored their sensitivity to the drug. In animal models, tumor growth was significantly reduced without major weight loss or other signs of toxicity.
The researchers say CS18 warrants further development as a potential component of combination cancer therapies, which could help prevent resistance from developing or make resistant tumors responsive to treatment again.
