Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

Abstract

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 (Fe 2+ ) induced by and dependent on oncogenic KRAS signaling. We leveraged an FDA-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.driven PDA xenografts as compared to breast cancer xenografts with wt KRAS (Figure 1E). To assess levels of reduced iron in the same tumors, we used 18 F-TRX, our recently described (Muir et al., 2019) oxidation-state specific radiotracer for Fe 2+ . We found that the mKRAS-driven PDA tumors were enriched in Fe 2+ as compared to the wt KRAS tumors, mirroring our findings with 68 Ga (Figure S1A). Together these findings suggest that increased iron uptake and iron reduction are common in PDA and associated with poor patient prognosis.