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

  • J Exp Med. 2022 Apr 4;219(4):e20210739. doi: 10.1084/jem.20210739.
Honglin Jiang  1  2 ,  Ryan K Muir  3 ,  Ryan L Gonciarz  3 ,  Adam B Olshen  2  4 ,  Iwei Yeh  2  5 ,  Byron C Hann  2 ,  Ning Zhao  6 ,  Yung-Hua Wang  6 ,  Spencer C Behr  6 ,  James E Korkola  7 ,  Michael J Evans  2  6 ,  Eric A Collisson  1  2 ,  Adam R Renslo  2  3
Affiliations
  • 1. Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.
  • 2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • 3. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA.
  • 4. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
  • 5. Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA.
  • 6. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA.
  • 7. Center for Spatial Systems Biomedicine, Oregon Health & Sciences University, Portland, OR.
PMID: 35262628 DOI: 10.1084/jem.20210739
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.

Products