Exploiting KRAS-Driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)
Year: 2020
Type: article
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.
DOI: 10.1084/jem.20210739
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: U.S. Department of Defense, American Cancer Society, National Institutes of Health, University of California, San Francisco, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Bioengineering, Congressionally Directed Medical Research Programs
Awards: The structural and functional basis of MET exon 14 activation and acquired drug resistance, G1439957436, G2139488668, G2342450115, G2643132104, Developing a pretargeting strategy to detect Fe(II) for nuclear medicine applications, Crucial Microenvironmental Cofactors for Pancreatic Cancer Pathogenesis, Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14, PRECISION TARGETING OF CASTRATION-RESISTANT PROSTATE CANCER WITH A NOVEL FERROUS IRON-DEPENDENT THERAPEUTIC DELIVERY AND TUMOR IMAGING STRATEGY, G5036689762, G6992277305, Chemical Methods for Ferrous Iron Dependent Drug Delivery, G7248061228, G7306389306, G7520244719, Visualization hub for genomics data exploration and translational discovery, Precision Targeting of Castration-Resistant Prostate Cancer with a Novel Ferrous Iron-Dependent Therapeutic Delivery and Tumor Imaging Strategy, PRECISION TARGETING OF CASTRATION-RESISTANT PROSTATE CANCER WITH A NOVEL FERROUS IRON-DEPENDENT THERAPEUTIC DELIVERY AND TUMOR IMAGING STRATEGY, Tailoring Therapy to Pancreatic Cancer Subtypes, G8609827848, Precision Targeting of Castration-Resistant Prostate Cancer with a Novel Ferrous Iron-Dependent Therapeutic Delivery and Tumor Imaging Strategy, Understanding efficacy and FE(II)-Promoted Activation of 1,2,4-Trioxolanes in cancer, Cancer Center Support Grant, BAY AREA & ANDERSON TEAM AGAINST ACQUIRED RESISTANCE - U54 PROGRAM (BAATAAR-UP), Genomics and Functional Characterization of NF1-mutated Lung Cancer
OpenAlex ID: W4220735026