Leveraging platinum-protein interactions to overcome chemoresistance
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.
Authors
- Jonathan Braverman (ORCID: https://orcid.org/0000-0002-0759-7220)
- Shinya Imada
- Stephen J. Lippard (ORCID: https://orcid.org/0000-0002-2693-4982)
- Ozen Leylek (ORCID: https://orcid.org/0000-0001-5772-725X)
- Jacob M. Goldberg (ORCID: https://orcid.org/0000-0002-8004-3769)
- George Eng (ORCID: https://orcid.org/0000-0003-0272-9623)
- D.H. Zhang (ORCID: https://orcid.org/0009-0005-7259-0948)
- Daniel S. Honeycutt (ORCID: https://orcid.org/0000-0001-6143-4492)
- Michael T. Hemann (ORCID: https://orcid.org/0000-0001-6776-2163)
- Fang Wang (ORCID: https://orcid.org/0000-0002-9192-6858)
- Camellia Huang (ORCID: https://orcid.org/0009-0008-0912-863X)
- W. H. McCarthy (ORCID: https://orcid.org/0009-0001-7778-0821)
- Jason M. Mrosla (ORCID: https://orcid.org/0009-0001-1957-355X)
- Brian Pallares (ORCID: https://orcid.org/0009-0003-8651-7392)
- Anna A. Griadunova
- Ömer H. Yilmaz
- Nicholas L. Petrone
Institutions
- Beth Israel Deaconess Medical Center (US)
- University of Rhode Island (US)
- Beth Israel Deaconess Hospital (US)
- Colgate University (US)
- Innovative Genomics Institute (US)
- Massachusetts Institute of Technology (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1038/s41467-025-64295-0
- Citations
- 4
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Rhode Island Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Emerson Collective
- National Institutes of Health
- National Cancer Institute
- National Institute of General Medical Sciences