A new study published in the Journal of Experimental & Clinical Cancer Research has identified the FGD3 protein as a promising predictive biomarker that potentially enhances the efficacy of chemotherapy and other cancer treatments that induce lytic cell death.
“We found, with all types of chemotherapy and all classes of breast cancer, there’s a very high correlation between the level of FGD3 and whether the patient responds favorably to chemotherapy,” said David J. Shapiro, PhD, professor of biochemistry at the University of Illinois Urbana-Champaign and senior author of the study. “Those with a high level are highly responsive; those with a low level are poorly responsive. This will allow us to identify those patients most likely to benefit from these kinds of cancer therapies.”
This discovery draws from previous research dating back to 2021, when Shapiro and colleagues identified a cancer drug candidate that can kill up to 100% of breast cancer cells in mice, including metastases, without major side effects. The drug, known as ErSO, is currently in preclinical stages of development as a treatment for estrogen receptor positive (ER+) breast cancer.
ErSO binds to the estrogen receptor to upregulate the anticipatory unfolded protein response (a-UPR) pathway, which normally protects cancer cells from stress while they rapidly grow. However, the researchers found cranking up the volume on this pathway can actually trigger lytic cell death.
“Most anticancer drugs inhibit something that the cell needs to survive, and they either prevent the cell from growing or, in some cases, cause it to die in an orderly way called apoptosis,” said Shapiro. “ErSO does exactly the opposite. It overactivates the cell pathway and the cancer cells literally swell up and rip open.”
In the current study, his team sought to identify key molecules involved in the mechanism of action of ErSO. A genome-wide CRISPR knockout screen in human breast cancer cells brought their attention to FGD3, a favorable prognostic biomarker for breast cancer whose role still remained unknown.
“The top target from the screen with ErSO was the gene for this little-studied protein called FGD3,” said Shapiro. “So, we manipulated levels of FGD3 in cancer cells and saw that it indeed controlled whether ErSO could kill the cells, and in a series of important experiments, we showed that FGD3 weakens the cell’s architecture.”
Experiments in human cells and patient-derived organoids showed that FGD3 is necessary for swollen cancer cells to rupture, releasing molecules that trigger the immune system to react against the tumor by recruiting natural killer cells and macrophages. In the presence of ErSO, FGD3 was found to activate the reorganization of actin filaments that provide structure to the cell in a way that facilitates the rupture of the cell membrane.
In a mouse model of human breast cancer, higher levels of FGD3 were found to enhance the anticancer effects of ErSO, as well as those of the chemotherapy drugs doxorubicin and epirubicin. A similar effect was found when analyzing patient data, showing that higher FGD3 levels correlated with better prognosis and response to chemotherapy.
“One of the things we saw was that FGD3 dramatically increased the movement to the cancer cell membrane of a protein that stimulates natural killer cells to target a cancer cell for destruction,” explained Shapiro. “This has the potential for enhancing immunotherapy for cancer and for reducing the doses of toxic drugs that you need to use. This is especially important in breast cancer because immunotherapy has had limited success against solid tumors.”
These findings support the use of FGD3 as a biomarker to identify cancer patients most likely to benefit from anticancer agents that induce immunogenic cell death, including chemotherapy, radiotherapy, and photodynamic therapy as well as a number of targeted treatments. Going forward, Shapiro and colleagues aim to explore whether FGD3 also plays a role in other solid tumors beyond breast cancer and other types of cancer therapy.
