A clinical-stage oncology compound selectively targets drug-resistant cancers.
| Title: | A clinical-stage oncology compound selectively targets drug-resistant cancers. |
|---|---|
| Authors: | Long K; Stanford University School of Medicine, Stanford, California 94305, USA.; Bhattacharjee D; Stanford University School of Medicine, Stanford, California 94305, USA.; Newman-Stonebraker SH; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Suhr S; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Mercado BQ; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Scheib E; Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA.; Tighe A; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK.; Romero L; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Thompson SL; Stanford University School of Medicine, Stanford, California 94305, USA.; Sausville EL; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; John KM; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.; Julian L; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Mishra S; Stanford University School of Medicine, Stanford, California 94305, USA.; Klingbeil O; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.; Laboratory for Functional Genomics and Gene Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.; Gupta P; Stanford University School of Medicine, Stanford, California 94305, USA.; Bhatt U; University Hospital Zurich, 8032 Zürich, CH.; Gao AC; University of California Davis, Sacramento, California 95817, USA.; Ricardo S; Applied Molecular Biosciences Unit (UCIBIO), Toxicologic Pathology Research Laboratory, Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), 4585-116 Gandra, Portugal.; Associate Laboratory i4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences (IUCS), University Polytechnic Higher Education Cooperative (CESPU), CRL, 4585-116 Gandra, Portugal.; Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.; Bornhauser BC; University Hospital Zurich, 8032 Zürich, CH.; Corsello SM; Stanford University School of Medicine, Stanford, California 94305, USA.; Taylor SS; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK.; Chen J; Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA.; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.; Holland PL; Yale University School of Medicine, New Haven, Connecticut 06511, USA.; Sheltzer JM; Stanford University School of Medicine, Stanford, California 94305, USA. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2026 Feb 03. Date of Electronic Publication: 2026 Feb 03. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Re-evaluating existing clinical compounds can uncover previously unrecognized mechanisms that reshape a drug's therapeutic potential. The small molecule Procaspase-Activating Compound 1 (PAC-1) entered oncology testing as a proposed activator of caspase-driven apoptosis. Here, we show that PAC-1-driven cytotoxicity occurs in the absence of executioner caspase expression, demonstrating that its anti-cancer activity occurs via an alternative mechanism. We provide genetic, biochemical, and biophysical evidence demonstrating that PAC-1 functions as a highly selective iron chelator that eliminates cancer cells by disrupting iron homeostasis. Unexpectedly, we discovered that expression of the key chemotherapy-resistance pump MDR1 confers marked hypersensitivity to PAC-1 treatment. While PAC-1 is only weakly effluxed by MDR1 under basal conditions, this process is potentiated when PAC-1 is bound to iron. Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1's mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation. |
| Competing Interests: | D.B., K.L., S.N.S., S.S., P.L.H., and J.M.S have filed intellectual property regarding methods to treat drug-resistant cancers based on the results presented in this manuscript. J.M.S. has received consulting fees from Merck, Pfizer, Ono Pharmaceuticals, Highside Capital Management, and Meliora Therapeutics and is a member of the advisory boards of BioIO, Permanence Bio, Karyoverse Therapeutics, and the Chemical Probes Portal. C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; has received research funding from Boehringer Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. The other authors declare no competing interests. |
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| Grant Information: | R01 GM065313 United States GM NIGMS NIH HHS; R01 CA225836 United States CA NCI NIH HHS; R01 CA237652 United States CA NCI NIH HHS; P30 CA016359 United States CA NCI NIH HHS; F32 GM150246 United States GM NIGMS NIH HHS; R01 CA276666 United States CA NCI NIH HHS; P30 CA045508 United States CA NCI NIH HHS |
| Entry Date(s): | Date Created: 20251215 Date Completed: 20260223 Latest Revision: 20260224 |
| Update Code: | 20260224 |
| PubMed Central ID: | PMC12699294 |
| DOI: | 10.1101/2025.11.26.690878 |
| PMID: | 41394735 |
| Database: | MEDLINE |
Journal Article; Preprint