| Title: |
A clinical-stage oncology compound selectively targets drug-resistant cancers. |
| Authors: |
Long, Kaitlin; Bhattacharjee, Debanjan; Newman-Stonebraker, Samuel H.; Suhr, Simon; Mercado, Brandon Q.; Scheib, Emily; Tighe, Anthony; Romero, Luciano; Thompson, Sarah L.; Sausville, Erin L.; John, Kristen M.; Julian, Linda; Mishra, Sanat; Klingbeil, Olaf; Gupta, Punya; Bhatt, Uditi; Gao, Allen C.; Ricardo, Sara; Vakoc, Christopher R.; Bornhauser, Beat C.; Corsello, Steven M.; Taylor, Stephen S.; Chen, Jue; Holland, Patrick L.; Sheltzer, Jason M. |
| Source: |
bioRxiv |
| Publication Year: |
2026 |
| Description: |
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. ; sponsorship: NIGMS NIH HHS|R01 GM065313, NCI NIH HHS|R01 CA225836, NCI NIH HHS|R01 CA237652, NCI NIH HHS|P30 CA016359, NIGMS NIH HHS|F32 GM150246, NCI NIH HHS|R01 CA276666, NCI NIH HHS|P30 CA045508 |
| Document Type: |
report |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/20.500.12942/783699; https://doi.org/10.1101/2025.11.26.690878; https://pubmed.ncbi.nlm.nih.gov/41394735 |
| DOI: |
10.1101/2025.11.26.690878 |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/783699; https://hdl.handle.net/20.500.12942/783699; https://lirias.kuleuven.be/retrieve/59ba2771-45ee-432c-b30f-55ffab653ae4; https://doi.org/10.1101/2025.11.26.690878; https://pubmed.ncbi.nlm.nih.gov/41394735 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.91377154 |
| Database: |
BASE |