New Inhibitors Could Enhance Chemotherapy’s Attack on Resistant Cancer Cells

Scientists at Johns Hopkins University School of Medicine and the Johns Hopkins Kimmel Cancer Center report the discovery of a promising therapeutic target that could strengthen the activity of a widely used chemotherapy, potentially improving treatment for certain treatment-resistant cancers. The work focuses on DCTPP1, a protein involved in DNA quality control. By degrading modified DNA fragments, DCTPP1 limits how effectively the drug reaches and damages cancer cells.

Decitabine, an established chemotherapy used for bone marrow disorders and acute myeloid leukemia, works by incorporating into the genome and triggering cell death. However, the researchers explain that DCTPP1 recognizes chemically modified pieces of DNA generated during this process and degrades them, reducing decitabine’s anticancer potency. In prostate cancer cells, where drug responses can become weaker, this degradation may contribute to incomplete therapeutic effects.

To identify ways to disable DCTPP1, the team began with structural biology and chemical screening. They screened 10,000 compounds to find candidates that inhibit DCTPP1 activity. Three distinct chemical classes emerged, suggesting that the protein can be blocked through specific binding interactions.

The researchers then used X-ray crystallography to determine atomic-resolution structures of DCTPP1 bound to these inhibitors. This approach revealed that each inhibitor class occupies a particular nucleotide-binding pocket. With binding modes clarified at the atomic level, the team combined the DCTPP1 inhibitors with decitabine in living prostate cancer cell cultures.

Their experiments indicate that adding DCTPP1 inhibitors boosts decitabine’s effectiveness at killing prostate cancer cells. The findings support the idea that stopping DCTPP1 prevents degradation of decitabine-related DNA modifications, allowing the chemotherapy’s genome-integrating mechanism to proceed more fully.

The study was published June 15 in Proceedings of the National Academy of Sciences as part of NIH-funded research. The authors emphasize that future work will test whether these inhibitor scaffolds can be optimized to further increase potency and potentially extend benefits to additional cancer types beyond prostate cancer.

For patients facing castration-resistant prostate cancer, a form that can metastasize and has a low five-year survival rate, improved drug combinations could be clinically valuable. By repurposing and enhancing an existing therapy rather than developing entirely new drugs, the approach offers a strategic path toward more durable responses.

Funding included support from the National Cancer Institute and additional foundations, reflecting the multi-institutional effort behind the program.