Researchers have identified a new way to overcome chemotherapy resistance by targeting a protein called p300. Their study, published in Genes & Development, shows that blocking p300 pushes cancer cells into a fatal state of internal stress.
Normally, when chemotherapy damages a cell’s DNA, p300 helps pause the cell’s activity so the damage can be checked and repaired. When p300 is blocked, the cell does not pause. Instead, it continues reading damaged DNA and producing proteins.
This causes a buildup of misfolded and toxic proteins inside the cell. The endoplasmic reticulum—the part of the cell responsible for folding proteins—becomes overloaded. The resulting stress response ultimately kills the cancer cell.
In laboratory models of chemotherapy-resistant colorectal cancer and pediatric osteosarcoma, chemotherapy or p300 inhibitors alone had limited effects. However, the combination of both treatments significantly shrank tumors and improved survival.
Importantly, this strategy does not require higher chemotherapy doses. Instead, it makes resistant cancer cells more sensitive to the doses patients can already tolerate.
Rather than focusing only on DNA repair, this approach takes advantage of the stress created when damaged cancer cells continue functioning without stopping. The findings suggest a promising new combination strategy for patients whose tumors no longer respond to platinum-based chemotherapy, without adding extra toxicity.