Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 09, 2022
- Source ID
- 10.1084/jem.20210739
Entities
People
- Adam Olshen
- Adam R Renslo
- Byron Hann
- Eric Collisson
- Honglin Jiang
- Iwei Yeh
- James E Korkola
- Michael J Evans
- Ning Zhao
- Ryan K. Muir
- Ryan L. Gonciarz
- Spencer C Behr
- Yung-hua Wang
Organizations
- American Cancer Society
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- Oregon Health & Science University
- University of California, San Francisco