Leveraging platinum-protein interactions to overcome chemoresistance

Fang Wang (), Jonathan Braverman (), George Eng, Ozen Leylek, Nicholas L. Petrone, Daniel S. Honeycutt, Shinya Imada, Brian Pallares, Daiyao Zhang, Jason M. Mrosla, Camellia S. Huang, Anna A. Griadunova, William K. McCarthy, Jacob M. Goldberg, Michael T. Hemann, Stephen J. Lippard () and Ömer H. Yilmaz ()
Additional contact information
Fang Wang: Massachusetts Institute of Technology
Jonathan Braverman: Massachusetts Institute of Technology
George Eng: Massachusetts Institute of Technology
Ozen Leylek: Massachusetts Institute of Technology
Nicholas L. Petrone: University of Rhode Island
Daniel S. Honeycutt: University of Rhode Island
Shinya Imada: Massachusetts Institute of Technology
Brian Pallares: Colgate University
Daiyao Zhang: Massachusetts Institute of Technology
Jason M. Mrosla: Colgate University
Camellia S. Huang: Massachusetts Institute of Technology
Anna A. Griadunova: Berkeley
William K. McCarthy: Colgate University
Jacob M. Goldberg: Colgate University
Michael T. Hemann: Massachusetts Institute of Technology
Stephen J. Lippard: Massachusetts Institute of Technology
Ömer H. Yilmaz: Massachusetts Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, enabling the removal of cytotoxic agents, such as anthracycline drugs. However, platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, we design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone. These drug conjugates retain the anticancer activity of anthracyclines and exhibit the ability to both circumvent drug efflux and delay the acquisition of drug resistance. In vivo experiments demonstrate that such drug conjugates extend survival in a preclinical organoid-based model of metastatic colon cancer in mice. Mechanistic studies indicate that these drug conjugates overcome resistance through covalent platinum-protein interactions, leading to significantly improved drug retention and alteration of subcellular drug distribution. This application of platinum offers many opportunities to confront issues related to chemoresistance and alternative pathways for augmenting conventional chemotherapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-64295-0

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