KRAS mutations cause a quarter of cancer mortality and currently are not sensitive to any targeted, FDA-approved agents. Several inhibitors of the MAPK pathway are FDA approved but exhibit low clinical tolerability at doses needed to adequately extinguish KRAS signaling. We discovered an avidity for ferrous iron (Fe2+) induced by and dependent on oncogenic KRAS signaling. We leveraged anFDA-approved MEK inhibitor to produce a prototypical Ferrous Iron–Activatable Drug Conjugate (FeADC) and with this novel agent achieved MAPK blockade in tumor cells while sparing normal tissues. These improvements allowed sustainable, effective treatment of tumor bearing animals with superior tolerability. Iron-activated therapeutics are unknown outside of antiparasitic therapy, but may hold significant promise for the treatment of KRAS-driven solid tumors.
Keywords: Pancreatic ductal adenocarcinoma, Lung adenocarcinoma, Iron metabolism, MAPK Pathway
Jiang, Honglin and Muir, Ryan K. and Gonciarz, Ryan L. and Olshen, Adam and Yeh, Iwei and Hann, Byron C. and Zhao, Ning and Wang, Yung-hua and Behr, Spencer C. and Evans, Michael J. and Collisson, Eric A. and Renslo, Adam R., Exploiting KRAS-Driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC). Available at SSRN: https://ssrn.com/abstract=3581366 or http://dx.doi.org/10.2139/ssrn.3581366
This version of the paper has not been formally peer reviewed.
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