Imagine a world where we could predict with remarkable accuracy which breast cancer patients will respond best to chemotherapy or immunotherapy. This isn’t science fiction; it’s the promise of a groundbreaking discovery about a protein called FGD3. A recent study published in the Journal of Experimental & Clinical Cancer Research (https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03559-5) reveals that FGD3 levels in breast cancer cells can act as a powerful biomarker, potentially revolutionizing treatment strategies.
But here’s where it gets even more exciting: this finding builds on earlier research from 2021, where the same team, led by Dr. David J. Shapiro of the University of Illinois Urbana-Champaign, developed a drug called ErSO. This drug, currently in preclinical trials for estrogen receptor-positive (ER+) breast cancer, showed astonishing results in mice, eliminating up to 100% of breast cancer cells, including metastases, with minimal side effects (https://news.illinois.edu/new-approach-eradicates-breast-cancer-in-mice/).
ErSO works by hijacking a cellular defense mechanism called the anticipatory unfolded protein response (a-UPR). Normally, this pathway shields cancer cells from stress during rapid growth. However, ErSO turns this shield into a weapon, overactivating the pathway until the cancer cells literally swell and burst open—a process known as lytic cell death.
“Most cancer drugs work by inhibiting essential cellular processes, either stopping growth or inducing apoptosis, a controlled form of cell death,” explains Shapiro. “ErSO does the opposite. It pushes the cell’s machinery into overdrive, causing the cancer cells to rupture dramatically.”
In their latest study, Shapiro’s team used a genome-wide CRISPR knockout screen to identify key players in ErSO’s mechanism. The standout discovery? FGD3, a protein previously recognized as a favorable prognostic biomarker for breast cancer but whose exact role remained a mystery.
“FGD3 emerged as the top candidate from our screen,” Shapiro notes. “When we manipulated its levels in cancer cells, we found it directly controlled whether ErSO could induce cell death. Further experiments revealed that FGD3 weakens the cell’s structural integrity, making it more susceptible to rupture.”
The team’s experiments in human cells and patient-derived organoids showed that FGD3 is essential for the swollen cancer cells to burst, releasing molecules that alert the immune system. This triggers a robust immune response, recruiting natural killer cells and macrophages to attack the tumor. Specifically, FGD3 activates the reorganization of actin filaments, the cell’s structural framework, in a way that facilitates membrane rupture.
In a mouse model of human breast cancer, higher FGD3 levels amplified the anticancer effects of ErSO, as well as traditional chemotherapy drugs like doxorubicin and epirubicin. This correlation was further validated in patient data, where elevated FGD3 levels were linked to better prognosis and response to chemotherapy.
And this is the part most people miss: FGD3 doesn’t just enhance chemotherapy; it also boosts immunotherapy. Shapiro explains, “We observed that FGD3 increases the movement of a protein to the cancer cell membrane, signaling natural killer cells to target and destroy the cancer cell. This could significantly improve immunotherapy outcomes and reduce the need for high doses of toxic drugs—a game-changer for breast cancer, where immunotherapy has struggled against solid tumors.”
These findings position FGD3 as a versatile biomarker, potentially applicable to various cancer treatments that induce immunogenic cell death, including chemotherapy, radiotherapy, photodynamic therapy, and targeted therapies. Moving forward, Shapiro’s team plans to investigate FGD3’s role in other solid tumors and cancer therapies.
But here’s the controversial question: Could FGD3-based treatments eventually replace traditional chemotherapy in certain cases? While it’s too early to say, this research opens the door to personalized treatment plans that maximize efficacy while minimizing side effects.
What do you think? Could FGD3 be the key to transforming cancer treatment? Share your thoughts in the comments below—we’d love to hear your perspective!