@article{a51c1ec44ac547c5962adcf6598a120c,
title = "Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors",
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.",
keywords = "Metabolism, Solid tumors",
author = "Honglin Jiang and Muir, {Ryan K.} and Gonciarz, {Ryan L.} and Olshen, {Adam B.} and Iwei Yeh and Hann, {Byron C.} and Ning Zhao and Wang, {Yung Hua} and Behr, {Spencer C.} and Korkola, {James E.} and Evans, {Michael J.} and Collisson, {Eric A.} and Renslo, {Adam R.}",
note = "Funding Information: Disclosures: R.K. Muir reported a patent to WO2019/005977 issued. S.C. Behr reported grants from CTT, and personal fees from AAA Novartis and Genvivo outside the submitted work. J. Korkola reported “other” from Convergent Genomics outside the submitted work. M.J. Evans reported a patent to Trioxolane Agents (PCT/US2018/039768) pending. E.A. Collisson reported grants from Astra Zeneca and Bayer outside the submitted work. E.A. Collisson and A.R. Renslo are cofounders of Tatara and have an ownership interest in the company. A.R. Renslo reported personal fees from Tatara Therapeutics outside the submitted work; in addition, A.R. Renslo had a patent number 10,287,312 issued, a patent number 10,662,215 issued, a patent number 11,014,955 issued, and a patent number 11,072,594 issued. No other disclosures were reported. Funding Information: This work was supported by National Institutes of Health (NIH), National Cancer Institute grants R01 (CA178015, CA222862, CA227807, CA239604, CA230263), U24 (CA210974), and U54 (CA224081; E.A. Collisson); NIH grant P30CA082103 (A.B. Olshen); NIH (AI105106) and Congressionally Directed Medical Research Program (W81XWH1810763 and W81XWH1810754) grants (A.R. Renslo); American Cancer Society Research Scholar grant 130635-RSG-17-005-01-CCE (M.J. Evans); and the Shoren-stein, Rhombauer, and Preston Families. Content does not reflect the views of the funders. Publisher Copyright: {\textcopyright} 2022 Jiang et al.",
year = "2022",
month = apr,
day = "4",
doi = "10.1084/jem.20210739",
language = "English (US)",
volume = "219",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",
}