Researchers at the University of California, San Francisco (UCSF) have successfully leveraged an FDA-approved drug to halt growth of tumors driven by mutations in the RAS gene, which are famously difficult to treat and account for about one in four cancer deaths.
The achievement takes advantage of the discovery that cells carrying KRAS gene mutations —which are the most common mutation found in human cancer—accumulate large amounts of a reactive form of iron, and that this “ferroaddiction” can be exploited to specifically deliver anticancer drugs to the ferroaddicted cells without harming normal, healthy cells. For their reported study the team tweaked an anticancer drug, cobimetinib, to generate a ferrous iron-activatable drug conjugate (FeADC), that only acts in these iron-rich cells, leaving other cells to function normally. The therapeutic strategy could feasibly be used to treat a wide variety of cancers driven by mutations in the KRAS gene, the researchers suggested.
“In this study, we describe a therapeutic strategy that enables more tolerable and efficacious combination therapies targeting the signaling pathways in KRAS-driven tumors,” said Eric Collisson, MD, a member of the UCSF Helen Diller Family Comprehensive Cancer Center. “The discovery of pharmacologically exploitable ferroaddiction in KRAS-driven cancers holds promise to improve the treatment of deadly cancers through a practicable and generalizable approach to FeADC design, development, and clinical testing.”
Collisson is a senior author of the team’s published report in the Journal of Experimental Medicine (JEM), which is titled “Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors,” in which the investigators concluded, “Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.”
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 drive a quarter of all cancer deaths, by activating cell signaling pathways that drive cell proliferation and enhance 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, such drugs are highly toxic to healthy cells and tissues, limiting their use at doses needed to inhibit signaling in cancer cells. “Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell,” the authors wrote.
Collisson further explained, “… inhibitors of the MEK1/2 enzymes have shown clinical benefit, but the approach suffers from dose-limiting toxicities in the eye, skin, gut, and other organs. Clinical experience has shown that sustainable dosing of these inhibitors is often well below FDA-approved dose, severely hampering the dose intensity achievable in the tumor cell and ultimately limiting clinical efficacy.”
KRAS mutations are “a cardinal feature of PDA,” the authors noted. This type of tumor is among the most aggressive and lethal solid tumor, with a 5-yr survival rate of ∼9%. The researchers further pointed out that systemic therapies are only marginally effective against the disease, and no targeted therapies against somatic aberrations are currently available.
As part of their reported study, first author Honglin Jiang, MD, and colleagues discovered that a wide variety of KRAS-driven tumors show increased activity of genes involved in iron uptake and metabolism, and, in PDA, this increase in gene activity correlated with shorter survival times. PET scans of PDA patients showed that their tumors accumulated high levels of iron. Jiang and colleagues wondered whether this addiction to iron might provide a way to target these cancer cells more precisely.
“We found that the elevated levels of iron, particularly 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),” explained study lead Adam R. Renslo, PhD, a professor in the Department of Pharmaceutical Chemistry at UCSF.
FeADCs are inactive versions of drugs that break apart in the presence of Fe2+, releasing the drug’s active version. The approach was inspired by anti-malarial drugs like artemisinin that target Fe2+ in the parasite as it invades red blood cells and degrades hemoglobin, producing large amounts of free heme iron.
Renslo and the team synthesized an FeADC version of the FDA-approved MEK inhibitor cobimetinib. “Cobimetinib is a classic example of an anticancer drug that we know works well on its target, but it hasn’t achieved its clinical potential because the same target is important in the skin and other normal tissues,” said Renslo.
The team’s new version of cobimetinib bears a small, molecular sensor of ferrous iron. The sensor effectively turns cobimetinib off until it encounters ferrous iron in the cancer cells. Laboratory tests showed that the new drug conjugate, named TRX-cobimetinib, had little effect on human skin or retinal cells but was activated inside KRAS mutant cancer cells, inhibiting the KRAS–MEK signaling pathway and blocking cell growth. “We converted an FDA-approved MEK inhibitor into a ferrous iron– activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues,” they stated.
The researchers then tested TRX-cobimetinib in several different mouse models of KRAS-driven cancer, including PDA and lung adenocarcinoma. In each case, TRX-cobimetinib inhibited tumor growth just as well as normal cobimetinib.
Unlike normal cobimetinib, however, TRX-cobimetinib caused no detectable damage to healthy tissues. This lack of toxicity allowed the researchers to combine TRX-cobimetinib treatment with other anticancer drugs. These combination therapies were even better at inhibiting tumor growth with little side effect on other tissues, and were better tolerated than comparable combinations using cobimetinib.
“Notably we show with TRX-COBI tumor-selective activation that enables ablation of MAPK signaling in PDA tumor cells and xenografts, while sparing the pathway in normal cells and tissues, including in major organs of iron storage (liver) and targets of MEK inhibitor–induced toxicity (skin and central nervous system,” the investigators reported.
“By removing toxicity from the equation, you’re talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic,” added Renslo. “That would be the home run for this approach.” Collisson added, “RAS mutations, by themselves, cause more misery than all other cancers combined, and take so many lives worldwide. This study brings us much closer to addressing the unmet need for better treatment of these cancers.”
The authors further concluded, “The discovery of pharmacologically exploitable ferroaddiction in RAS-driven cancers holds promise to improve the treatment of deadly cancers through a practicable and generalizable approach to FeADC design, development, and clinical testing.” Renslo is already at work studying whether a similar approach can be applied to antibiotics, some of which have untoward side effects, to target treatment and reduce toxicity.
Collisson, who works every day with cancer patients, said the collaboration with Renslo has given him hope that he’ll be able to give those patients better options in the not-too-distant future. And, he added, the experience has opened his eyes to things he’d been missing by being so focused on his day-to-day oncology world. “I love taking care of patients, and a fundamental part of that is, ultimately, getting a molecule to the place where it’s needed and keeping it out of places where it’s not needed,” he said. “To be able to deliver a therapy that’s five times more potent than what we currently have and not run the patient ragged, that’s pretty exciting.”