Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

Jiang, H.; Muir, R. K.; Gonciarz, R. L.; Olshen, A. B.; Yeh, I.; Hann, B. C.; Zhao, N.; Wang, Y.-h.; Korkola, J.; Behr, S. C.; Evans, M. J.; collisson, e.; Renslo, A.

doi:10.1101/2020.05.12.088971

bioRxiv · 10.1101/2020.05.12.088971

Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

Jiang, H.·Muir, R. K.·Gonciarz, R. L.·Olshen, A. B.·Yeh, I.·Hann, B. C.·Zhao, N.·Wang, Y.-h.·Korkola, J.·Behr, S. C.·Evans, M. J.·collisson, e.·Renslo, A.

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Abstract

KRAS mutations cause a quarter of cancer mortality and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at dosages required to adequately extinguish RAS/RAF/MAPK signaling. We found that oncogenic KRAS signaling induces ferrous iron (Fe2+) accumulation early in and throughout KRAS-mediated transformation. We used an FDA-approved MEK inhibitor to produce a prototypical Ferrous Iron-Activatable Drug Conjugate (FeADC) which 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 treatment of KRAS-driven solid tumors.

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Jiang, H., Muir, R. K., Gonciarz, R. L., Olshen, A. B., Yeh, I., Hann, B. C., Zhao, N., Wang, Y.-h., Korkola, J., Behr, S. C., Evans, M. J., collisson, e., Renslo, A.. 2020-05-14. Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC). https://doi.org/10.1101/2020.05.12.088971

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