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Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.
Jiang, Honglin; Muir, Ryan K; Gonciarz, Ryan L; Olshen, Adam B; Yeh, Iwei; Hann, Byron C; Zhao, Ning; Wang, Yung-Hua; Behr, Spencer C; Korkola, James E; Evans, Michael J; Collisson, Eric A; Renslo, Adam R.
Affiliation
  • Jiang H; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.
  • Muir RK; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Gonciarz RL; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA.
  • Olshen AB; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA.
  • Yeh I; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Hann BC; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
  • Zhao N; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Wang YH; Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA.
  • Behr SC; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
  • Korkola JE; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA.
  • Evans MJ; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA.
  • Collisson EA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA.
  • Renslo AR; Center for Spatial Systems Biomedicine, Oregon Health & Sciences University, Portland, OR.
J Exp Med ; 219(4)2022 04 04.
Article in En | MEDLINE | ID: mdl-35262628
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proto-Oncogene Proteins p21(ras) / Neoplasms Limits: Animals Language: En Journal: J Exp Med Year: 2022 Type: Article Affiliation country: Canada
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proto-Oncogene Proteins p21(ras) / Neoplasms Limits: Animals Language: En Journal: J Exp Med Year: 2022 Type: Article Affiliation country: Canada