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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere20210739
JournalJournal of Experimental Medicine
Volume219
Issue number4
DOIs
StatePublished - Apr 4 2022
Externally publishedYes

Keywords

  • Metabolism
  • Solid tumors

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors'. Together they form a unique fingerprint.

Cite this