Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors

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 (Fe-2(+)) 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.

Automated summary

KRAS mutations are a major driver of cancer mortality, but most of them cannot be targeted by drugs. This study discovered that oncogenic KRAS signaling leads to the accumulation of ferrous iron (Fe-2(+)). By converting an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC), the researchers were able to effectively block MAPK signaling in tumor cells and improve systemic tolerability. FeADC holds promise for improving the treatment of KRAS-driven solid tumors.