Cancer cells’ iron addiction could be an Achilles’ heel

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PET imaging (right) shows iron accumulation in metastatic tumors developing in the spine and liver of patients with pancreatic ductal adenocarcinoma. Credit: © 2022 Jiang et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20210739

Researchers at the University of California, San Francisco (UCSF) have found that cells carrying the most common mutation found in human cancer accumulate large amounts of ferrous iron, and this “ferroaddiction” can be harnessed to specifically deliver powerful anti-cancer drugs without harming the normal. , healthy cells. The therapeutic strategy, described in a study published on March 9, 2022 in the Journal of Experimental Medicine (YWAM), could be used to treat a wide variety of cancers caused by mutations in the kras embarrassed.

Mutations in kras are found in many cancers and are particularly common 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 pathways that stimulate cell proliferation and improve cell survival. These signaling pathways can be blocked by drugs that inhibit some of the proteins activated by KRAS, but, in addition to killing cancer cells, these drugs are highly toxic to healthy cells and tissues, limiting their use to the doses needed to inhibit signaling in cancer cells. .

“For example, inhibitors of MEK1/2 enzymes have shown clinical benefits, but the approach suffers from dose-limiting toxicities in the eyes, skin, gut, and other organs,” says Eric A. Collisson, MD, professor in the Department of Medicine at UCSF. “Clinical experience has shown that the sustained dosage of these inhibitors is often much lower than the FDA-approved dose, which severely hampers the achievable dose intensity in the tumor cell and ultimately limits clinical efficacy.”

In the new YWAM study, first author Honglin Jiang and colleagues are developing a method to target MEK inhibitors, and potentially other anti-cancer agents, to kras– leads to tumors without harming other healthy tissues of the body.

Researchers have found that a wide variety of krasIron-induced tumors show increased activity of genes involved in iron uptake and metabolism, and in PDA this increased gene activity correlates with shorter survival times. PET scans of PDA patients showed that their tumors were accumulating high levels of iron. Jiang and his colleagues wondered if this iron addiction might provide a way to target these cancer cells more precisely.

“We found that high levels of iron, particularly in its ferrous, Fe2+ oxidation state, are driven by oncogene kraswe therefore hypothesized that the mutant krasPDA-directed PDA tumor cells could be selectively targeted with a ferrous iron activatable drug conjugate (FeADC),” says Adam R. Renslo, a professor in the Department of Pharmaceutical Chemistry at UCSF who led the study.

FeADCs are inactive versions of drugs that break down in the presence of Fe2+, releasing the active version of the drug. The approach was inspired by antimalarial drugs like artemisinin which targets Fe2+ in the parasite when it invades red blood cells and breaks down hemoglobin, producing large amounts of free heme iron.

Renslo and the team synthesized an FeADC version of cobimetinib, an FDA-approved MEK inhibitor. Laboratory tests showed that this drug conjugate, called TRX-cobimetinib, had little effect on human skin or retinal cells, but was internally activated kras mutant cancer cells, inhibiting the KRAS–MEK signaling pathway and blocking cell growth.

The researchers then tested TRX-cobimetinib in several different mouse models of kras– driven by cancer, including PDA and lung adenocarcinoma. In each case, TRX-cobimetinib inhibited tumor growth as well as normal cobimetinib. Unlike normal cobimetinib, however, TRX-cobimetinib caused no detectable damage to other healthy tissues. This lack of toxicity allowed researchers to combine TRX-cobimetinib treatment with other cancer drugs. These combination therapies were even more effective in inhibiting tumor growth with few side effects on other tissues.

“In this study, we describe a therapeutic strategy that allows for more tolerable and effective combination therapies targeting signaling pathways in kras-directed tumors,” says Collisson. “The discovery of a pharmacologically exploitable ferroadediction in kras-driven cancers promises to improve the treatment of life-threatening cancers through a practical and generalizable approach to FeADC design, development and clinical trials.

For more on this research, see Treating stubborn tumors by harnessing the cancer cells’ “addiction” to iron.

Reference: “Activatable drug-ferrous iron conjugate achieves potent MAPK blockade in KRAS-induced tumors” 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, March 9, 2022, Journal of Experimental Medicine.
DOI: 10.1084/jem.20210739

Funding: NIH/National Cancer Institute, Congressional Medical Research Program, Shorenstein, Rhombauer and Preston families

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