A cellular protein, FGD3, enhances the effectiveness of breast cancer chemotherapy and immunotherapy, according to new research. The protein, naturally occurring in higher levels in breast cancer cells, boosts the impact of anticancer agents like doxorubicin and ErSO, a preclinical drug. FGD3 contributes to the rupture of cancer cells disrupted by these drugs, amplifying their efficacy and enhancing anticancer immunotherapies. The discovery is detailed in the Journal of Experimental & Clinical Cancer Research. The protein's role was uncovered through experiments with ErSO, an experimental drug that eliminates 95-100% of estrogen-receptor-positive breast cancer cells in a mouse model. ErSO upregulates a cellular pathway that normally protects cancer cells from stress, but when this pathway is overactivated, the system malfunctions. Most anticancer drugs inhibit cell survival mechanisms, causing cells to either stop growing or undergo controlled cell death (apoptosis). However, ErSO does the opposite; it overactivates the cell pathway, causing cancer cells to swell and burst. This unique mechanism was first discovered by University of Illinois Urbana-Champaign biochemistry professor David Shapiro and chemistry professor Paul Hergenrother in 2021. In the new study, they aimed to understand how ErSO works by identifying cellular proteins involved in cell survival decisions. They tested the drug against breast cancer cell lines with specific genes deleted, identifying the gene for FGD3 as a key player in ErSO's cancer-killing pathway. FGD3's role was further explored by manipulating its levels in cancer cells, revealing its control over ErSO's ability to kill cells. In a series of experiments, FGD3 was shown to weaken the cell's architecture, leading to cell rupture when under attack by chemotherapy or other anticancer therapies. This rupture alerts the immune system, which then sends in natural killer cells and macrophages to destroy the cancer cells. The experiments were conducted in 2D cell culture and 3D breast cancer patient-derived organoids, which closely mimic the tumor environment. Study co-author Dr. Olufunmilayo Olopade, director of the Center for Clinical Cancer Genetics and Global Health at University of Chicago Medicine, developed the organoids. The team also tested FGD3's role in a mouse model of human breast cancer, confirming that higher FGD3 levels enhanced ErSO's killing power. FGD3 was found to increase the movement of a protein that stimulates natural killer cells to target cancer cells for destruction, potentially enhancing immunotherapy and reducing toxic drug doses. This is particularly significant in breast cancer, where immunotherapy has had limited success against solid tumors. The research team analyzed human breast cancer data, finding a strong correlation between FGD3 levels and patient responses to chemotherapy. High FGD3 levels indicated favorable responses, while low levels predicted poor responses. This discovery enables the identification of patients most likely to benefit from these cancer therapies. The study's findings open up new avenues for research, with the team planning to explore FGD3's role in other cancers and cancer therapies. The research was supported by the National Institutes of Health, the Amend Family Charitable Fund, and Systems Oncology. The paper, 'FGD3 mediates lytic cell death, enhancing efficacy and immunogenicity of chemotherapy agents in breast cancer,' is available online with the DOI: 10.1186/s13046-025-03559-5.
