Dismantling Cancer Cells’ “Drug-Resistance Scaffold”: TopBP1 Inhibitor Restores Treatment Response in Animal Models

One of the most difficult turning points in cancer treatment occurs when a previously effective drug gradually stops working. A research team at Baylor College of Medicine is now attempting to target a survival mechanism shared by cancer cells: using the experimental small molecule CS18 to disrupt TopBP1 in hopes of weakening tumors’ ability to repair damage, sustain growth, and evade drug effects, thereby reopening a treatment window that had already closed.

TopBP1 is a scaffold protein without typical enzymatic activity. Through multiple BRCT domains, it recruits other proteins to coordinate DNA replication, damage repair, and cell-cycle checkpoints. Targets of this kind, which function through protein–protein interactions, are generally more difficult to drug than enzymatic active sites. Researchers designed CS18 to target the BRCT7/8 region of TopBP1, seeking to disrupt its critical interaction network rather than directly inhibit a catalytic reaction.

According to results released by the research team, CS18 can enhance the anticancer effects of PARP inhibitors. PARP inhibitors already exploit defects in tumor DNA repair to deliver a lethal blow, but cancer cells may develop drug resistance by rebuilding repair capacity or altering signaling pathways. In theory, disrupting TopBP1 could re-expose vulnerabilities in this backup system. However, the available data remain insufficient to determine which molecular features of tumors are best suited to this combination therapy.

Another experiment focused on lung cancer cells that had developed resistance to osimertinib. Osimertinib is an important targeted drug for treating non-small cell lung cancer with specific EGFR mutations, but acquired resistance is nearly inevitable. Researchers found that adding CS18 restored drug sensitivity in resistant cells, suggesting that TopBP1 may sit at the intersection of different resistance pathways rather than affecting only a single cancer type or drug.

In animal tumor models, treatments containing CS18 reduced tumor growth, and the research team did not observe major toxicity signals. This is a necessary step in supporting further development, but it cannot be equated with safety in humans. TopBP1 also participates in DNA replication and genomic stability in normal cells, so future studies must still clarify the drug’s selectivity, distribution in the body, tolerable dose, and whether long-term inhibition damages rapidly renewing normal tissues.

These findings currently provide preclinical proof of concept, not a new therapy available to patients. CS18 must still undergo pharmacokinetic and toxicological studies, as well as testing in a broader range of tumor models, before it can potentially enter human trials. Researchers must also establish biomarkers to identify which resistance mechanisms truly depend on TopBP1. If these hurdles can be overcome, the value of a TopBP1-inhibition strategy may lie not in replacing existing drugs, but in extending the period during which they remain effective.