June 16, 2024

Cancer Cells’ Iron Addiction May Be an Achilles Heel

PET imaging (right) reveals the build-up of iron in metastatic growths growing in the spinal column and liver of patients with pancreatic ductal adenocarcinoma. Credit: © 2022 Jiang et al.
Researchers at the University of California, San Francisco (UCSF), have found that cells carrying the most typical anomaly found in human cancer collect big amounts of ferrous iron which this “ferroaddiction” can be exploited to specifically provide effective anticancer drugs without damaging typical, healthy cells. The restorative strategy, explained in a study that was published on March 9, 2022, in the Journal of Experimental Medicine (JEM), could be utilized to treat a variety of cancers driven by anomalies in the KRAS gene.
Mutations in KRAS are discovered in lots of cancers and are especially typical in pancreatic ductal adenocarcinoma (PDA), colorectal cancer, severe myeloid leukemia, and lung adenocarcinoma. In overall, KRAS anomalies are believed to cause a quarter of all cancer deaths by triggering cell signaling pathways that drive cell expansion and improve cell survival. These signaling pathways can be obstructed by drugs that prevent some of the proteins activated by KRAS, however, in addition to killing cancer cells, these drugs are extremely harmful to healthy cells and tissues, limiting their use at dosages needed to hinder signaling in cancer cells.
” For example, inhibitors of the MEK1/2 enzymes have shown medical advantage, however the method experiences dose-limiting toxicities in the eye, skin, gut, and other organs,” describes Eric A. Collisson, MD, a teacher in the Department of Medicine at UCSF. “Clinical experience has revealed that sustainable dosing of these inhibitors is frequently well listed below FDA-approved dosage, severely hampering the dosage strength possible in the tumor cell and ultimately restricting clinical efficacy.”

In the new JEM study, very first author Honglin Jiang and coworkers establish a method to target MEK inhibitors, and potentially other anticancer representatives, to KRAS-driven tumors without damaging other, healthy tissues in the body.
The scientists discovered that a wide range of KRAS-driven tumors reveal increased activity of genes associated with iron uptake and metabolism, and, in PDA, this increase in gene activity correlated with much shorter survival times. Animal scans of PDA patients showed that their tumors accumulated high levels of iron. Jiang and coworkers questioned whether this addiction to iron might provide a way to target these cancer cells more exactly.
” We found that the elevated levels of iron, especially in its ferrous, Fe2+ oxidation state, are driven by oncogenic KRAS, so we hypothesized that mutant KRAS-driven PDA tumor cells might be selectively targeted with a ferrous iron– activatable drug conjugate (FeADC),” describes Adam R. Renslo, a professor in the Department of Pharmaceutical Chemistry at UCSF who led the study.
FeADCs are non-active versions of drugs that disintegrate in the existence of Fe2+, releasing the drugs active variation. The approach was influenced by anti-malarial drugs like artemisinin that target Fe2+ in the parasite as it invades red blood cells and deteriorates hemoglobin, producing large quantities of free heme iron.
Renslo and the team manufactured an FeADC variation of the FDA-approved MEK inhibitor cobimetinib. Lab tests showed that this drug conjugate, named TRX-cobimetinib, had little result on human skin or retinal cells however was activated inside KRAS mutant cancer cells, inhibiting the KRAS– MEK signaling path and blocking cell development.
The researchers then evaluated TRX-cobimetinib in several different mouse models of KRAS-driven cancer, consisting of PDA and lung adenocarcinoma. In each case, TRX-cobimetinib hindered tumor growth simply as well as normal cobimetinib. Unlike typical cobimetinib, nevertheless, TRX-cobimetinib caused no noticeable damage to other, healthy tissues. This absence of toxicity permitted the researchers to integrate TRX-cobimetinib treatment with other anticancer drugs. These combination treatments were even better at inhibiting tumor development with little adverse effects on other tissues.
” In this research study, we explain a therapeutic method that makes it possible for more efficacious and bearable combination treatments targeting the signaling paths in KRAS-driven tumors,” Collisson says. “The discovery of pharmacologically exploitable ferroaddiction in KRAS-driven cancers holds pledge to improve the treatment of lethal cancers through a practicable and generalizable approach to FeADC design, advancement, and clinical screening.”
For more on this research, see Treating Tough Tumors by Exploiting Cancer Cells Iron “Addiction.”.
Referral: “Ferrous iron– activatable drug conjugate achieves potent MAPK blockade in KRAS-driven growths” by Honglin Jiang, Ryan K. Muir, Ryan L. Gonciarz, Adam B. Olshen, Iwei Yeh, Byron C. Hann, Ning Zhao, Yung-hua Wang, Spencer C. Behr, James E. Korkola, Michael J. Evans, Eric A. Collisson and Adam R. Renslo, 9 March 2022, Journal of Experimental Medicine.DOI: 10.1084/ jem.20210739.
Funding: NIH/National Cancer Institute, Congressionally Directed Medical Research Program, Shorenstein, Rhombauer, and Preston Families.

Anomalies in KRAS are found in many cancers and are especially typical in pancreatic ductal adenocarcinoma (PDA), colorectal cancer, acute myeloid leukemia, and lung adenocarcinoma. In total, KRAS mutations are thought to cause a quarter of all cancer deaths by activating cell signaling paths that drive cell proliferation and improve cell survival. These signaling pathways can be obstructed by drugs that hinder some of the proteins triggered by KRAS, however, in addition to killing cancer cells, these drugs are extremely toxic to healthy cells and tissues, limiting their usage at doses needed to hinder signaling in cancer cells.
Jiang and coworkers wondered whether this addiction to iron might offer a method to target these cancer cells more exactly.
The scientists then checked TRX-cobimetinib in a number of various mouse models of KRAS-driven cancer, consisting of PDA and lung adenocarcinoma.