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

115 Pages Posted: 7 May 2020 Sneak Peek Status: Under Review

See all articles by Honglin Jiang

Honglin Jiang

University of California, San Francisco (UCSF) - Division of Hematology and Oncology

Ryan K. Muir

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Ryan L. Gonciarz

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Adam Olshen

University of California, San Francisco (UCSF) - Department of Medicine

Iwei Yeh

University of California, San Francisco (UCSF) - Department of Pathology

Byron C. Hann

University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center

Ning Zhao

University of California, San Francisco (UCSF)

Yung-hua Wang

University of California, San Francisco (UCSF)

Spencer C. Behr

University of California, San Francisco (UCSF)

Michael J. Evans

University of California, San Francisco (UCSF)

Eric A. Collisson

University of California, San Francisco (UCSF) - Division of Hematology and Oncology

Adam R. Renslo

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

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Abstract

KRAS mutations cause a quarter of cancer mortality and currently are not sensitive to any targeted, FDA-approved agents.  Several inhibitors of the MAPK pathway are FDA approved but exhibit low clinical tolerability at doses needed to adequately extinguish KRAS signaling. We discovered an avidity for ferrous iron (Fe2+) induced by and dependent on oncogenic KRAS signaling. We leveraged anFDA-approved MEK inhibitor to produce a prototypical Ferrous Iron–Activatable Drug Conjugate (FeADC) and with this novel agent achieved MAPK blockade in tumor cells while sparing normal tissues.  These improvements allowed sustainable, effective treatment of tumor bearing animals with superior tolerability. Iron-activated therapeutics are unknown outside of antiparasitic therapy, but may hold significant promise for the treatment of KRAS-driven solid tumors.

Keywords: Pancreatic ductal adenocarcinoma, Lung adenocarcinoma, Iron metabolism, MAPK Pathway

Suggested Citation

Jiang, Honglin and Muir, Ryan K. and Gonciarz, Ryan L. and Olshen, Adam and Yeh, Iwei and Hann, Byron C. and Zhao, Ning and Wang, Yung-hua and Behr, Spencer C. and Evans, Michael J. and Collisson, Eric A. and Renslo, Adam R., Exploiting KRAS-Driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC). CELL-D-20-01062. Available at SSRN: https://ssrn.com/abstract=3581366 or http://dx.doi.org/10.2139/ssrn.3581366
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Honglin Jiang

University of California, San Francisco (UCSF) - Division of Hematology and Oncology

United States

Ryan K. Muir

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry ( email )

San Francisco, CA 94143-2280
United States

Ryan L. Gonciarz

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry ( email )

San Francisco, CA 94143-2280
United States

Adam Olshen

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Iwei Yeh

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Byron C. Hann

University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center ( email )

Box 0981, UCSF
San Francisco, CA 94143-0981
United States

Ning Zhao

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Yung-hua Wang

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Spencer C. Behr

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Michael J. Evans

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Eric A. Collisson (Contact Author)

University of California, San Francisco (UCSF) - Division of Hematology and Oncology ( email )

United States

Adam R. Renslo

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry ( email )

San Francisco, CA 94143-2280
United States

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