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.
Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
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.
- Award Id(s): R01 [CA178015, CA222862, CA227807, CA239604, CA230263],U24 [CA210974],P30CA082103,AI105106
- Award Id(s): W81XWH1810763,W81XWH1810754
- Award Id(s): 130635-RSG-17-005-01-CCE
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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, Adam R. Renslo; Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J Exp Med 4 April 2022; 219 (4): e20210739. doi: https://doi.org/10.1084/jem.20210739
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