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.
Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors
Beteiligte:
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.
Beschreibung:
<jats:p>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.</jats:p>