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Ferroptosis induction as a strategy to treat pancreatic cancer

Resisting cell death, an original hallmark of cancer, is necessary for cancer growth. As a result, many therapeutic approaches have been made to induce cancer specific induction of cell death. This is especially important in pancreatic cancer, in which new targets are critically needed for this highly lethal cancer. There a multiple types of cancer cell death, for example, the caspase-dependent apoptosis, necroptosis, and pyroptosis and the lysosomal dependent autophagy. But today we are going to focus on the iron-dependent pathway ferroptosis.  

Ferroptosis is characterized by iron dependency and lipid reactive oxygen species (ROS) accumulation. This pathway was first discovered in 2012 by the Stockwell group in which they observed that the small molecule erastin induced a non-apoptotic form of cell death in the N-ras mutated fibrosarcoma cell line HT-1080 and that they could recover cell death via inhibition using the novel ferroptosis inhibitor ferrostatin-1. Ferrostatin-1 was also discovered to be neuroprotective, preventing glutamate-induced neurotoxicity. This led the researchers to question if either calcium influx or decreased cystine, oxidized cysteine, uptake were involved as these processes have been known to be initiators for glutamate-induced cell death. They discovered that inhibition of cystine uptake by multiple methods (erastin, SAS, or glutamate), but not calcium influx, could trigger ferroptosis and that promotion of cystine uptake could rescue iron-dependent cell death in cancer cells. Additionally, it has been shown that deletion of the cystine xc- gene Slc7a11 has no major toxicity in unstressed mice, further suggesting this could be a good target.

Most pancreatic ductal adenocarcinoma (PDAC) cases, more than 90%, have mutated KRAS, which has been shown in many studies to induce increased production of reactive oxygen species through increased cellular proliferation and reprogramming of cellular metabolism. Normal cells would die under high ROS levels, but cancer cells can counteract high levels of ROS via upregulating detoxifying metabolites like glutathione. Glutathione, a tripeptide of L-glutamate, cysteine, and glycine, has been shown to increase cancer cell resistance to oxidative stress. Additionally, the oxidized cystine has been shown to regulate intracellular GSH metabolism, further strengthening its role in ROS detoxification. 

Recently, Badgley et al. discovered that genetic and pharmacological depletion of cystine levels can induce ferroptosis in pancreatic cancer models to inhibit tumor growth. They hypothesized that import of cystine is important for PDAC cells to survive under high oxidative stress and could be a good therapeutic target. In this study, they used a chemically enhanced erastin analog imidazole ketone erastin (IKE) that has been modified to increase water solubility, metabolic stability, potency, and selectivity. In vitro, IKE treatment reduced cell viability in four out of five PDAC cell lines tested mimicking cystine starvation, with neither method inducing caspase 3 cleavage. 

They also examined the effect of reduced cystine transport in vivo by modifying the commonly used KPC mouse to delete the cystine transport gene Slc7a11 upon tamoxifen induction (KPFSR). Median survival time was doubled in tamoxifen treated mice compared to the control and this survival extension was reversed upon addition of the cysteine analog NAC further suggesting the increase in survival is linked to cysteine metabolism. Prior to this paper, there was no in vivo characterization of ferroptosis, but the authors observed distinct histopathological markers in the KPSFR mouse model. Additionally, they performed RNA sequencing on malignant cells and observed enrichment in the ferroptotic gene signature from the previously mentioned erastin treated HT-10800 cells. 

Drug delivery has always been a problem in PDAC due to extensive fibrosis and decreased tissue perfusion. To deplete cystine levels pharmacologically, the authors used the engineered enzyme cyst(e)inase, which has a favorable half-life and stability in vivo and has been shown to degrade both cystine and cysteine. Cyst(e)inase treatment in the KPC mouse model revealed similar histopathology to the KPFSR mouse and all four tumors treated with 100 mg/kg cyst(e)inase exhibited stabilized tumors. 

Further work is necessary to achieve a small molecule with ideal cystine depletion and ideal drug delivery in PDAC, but this work suggests that induction of ferroptosis in pancreatic cancer has selective anticancer activity both in vivo and in vitro. Additionally, this work provides a histopathological characterization of ferroptosis in vivo. 
REFERENECES:

Badgley MA, Kremer DM, Maurer HC, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020;368(6486):85-89. doi:10.1126/science.aaw9872

Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi:10.1016/j.cell.2012.03.042


Ye Z, Liu W, Zhuo Q, et al. Ferroptosis: Final destination for cancer?. Cell Prolif. 2020;53(3):e12761. doi:10.1111/cpr.12761

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