2. Academic Validation
  3. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors

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

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.

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