{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T13:20:04Z","timestamp":1770211204033,"version":"3.49.0"},"posted":{"date-parts":[[2025,11,30]]},"group-title":"Cancer Biology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1101\/2025.11.26.690878","type":"posted-content","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T03:05:13Z","timestamp":1764558313000},"source":"Crossref","is-referenced-by-count":0,"title":["A clinical-stage oncology compound selectively targets drug-resistant cancers"],"prefix":"10.64898","author":[{"given":"Kaitlin","family":"Long","sequence":"first","affiliation":[{"name":"Stanford University;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debanjan","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Stanford University;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel H.","family":"Newman-Stonebraker","sequence":"additional","affiliation":[{"name":"Yale 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