Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS -driven tumors
Open accessPublished version of a preprint
Abstract
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. 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. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. 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. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
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Collisson and Renslo's group developed an approach by linking an FDA-approved MEK inhibitor with a ferrous iron-activatable drug conjugate (FeADC).
“Lately in 2022, Collisson and Renslo’s group developed an innovative approach by linking an FDA-approved MEK inhibitor with a ferrous iron-activatable drug conjugate (FeADC).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [652]
Oncogenic KRAS signaling induces early ferrous iron (Fe2+) accumulation throughout mutant KRAS, allowing selective blockage of MAPK and targeting of KRAS-driven solid tumors.
“This conjugate was based on their discovery that oncogenic KRAS signaling induces early ferrous iron (Fe2+) accumulation throughout mutant KRAS, allowing selective blockage of MAPK and targeting of KRAS-driven solid tumors.652”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [652]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Jiang, H., Muir, R. K., Gonciarz, R. L., Olshen, A. B., Yeh, I., Hann, B. C., Zhao, N., Wang, Y.-H., Behr, S. C., Korkola, J. E., Evans, M. J., Collisson, E. A., & Renslo, A. R.
- Affiliations
- University of California, San Francisco (US)
- Oregon Health & Science University (US)
- Corresponding author
- Collisson, Eric A.
- Renslo, Adam R.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2022-03-09
- Volume
- 219
- Issue
- 4
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC8916116
- OpenAlex
- W4220735026
- Cited by
- 33
- References
- 72
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 10 · 2022: 5 · 2020: 1
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01 [CA178015, CA222862, CA227807, CA239604, CA230263], U24 [CA210974], P30CA082103, AI105106)
- Congressionally Directed Medical Research Program (W81XWH1810763, W81XWH1810754)
- American Cancer Society (130635-RSG-17-005-01-CCE)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS-driven tumors, MEK inhibitors, ferrous iron accumulation, Ras/Raf/MAPK signaling, solid tumors
- MeSH terms
- Animals, Iron, Mutation, Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Protein Kinase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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