Abstract:
My presentation addresses one of the most pressing challenges in oncology: Treatment Resistance. I will focus on a novel strategy to overcome oxaliplatin resistance in colorectal cancer, titled " Phytohormone strigolactams overcomes oxaliplatin-resistance in colorectal cancer by blocking the late-stage autophagy to tip the metabolic balance toward ferroptosis."
The clinical efficacy of oxaliplatin, a first-line chemotherapy for colorectal cancer, is severely limited by the development of intrinsic and acquired resistance. A key mechanism enabling this resistance is the upregulation of protective autophagy, which allows cancer cells to survive chemotherapy-induced stress by recycling damaged components. Simply blocking autophagy with non-specific agents has proven challenging due to toxicity.
Our research introduces a new approach. We developed a novel synthetic strigolactam analog, SL 39, which directly targets this resistance mechanism. SL 39 acts not as a broad autophagy poison, but as a precision inhibitor of late-stage autophagy, specifically blocking autophagosome-lysosome fusion. This unique action traps oxaliplatin-resistant cells with their own accumulated metabolic damage.
Crucially, we demonstrate that SL 39 does more than just inhibit autophagy—it actively reprograms the cell's fate. By shutting down this critical survival pathway, SL 39 tips the metabolic balance within resistant cells, converting the protective process into a lethal vulnerability. This leads to overwhelming oxidative stress, mitochondrial dysfunction, and, most importantly, the induction of ferroptosis—an iron-dependent cell death pathway to which these resistant cells are now uniquely sensitive.
Our data show that combining SL 39 with oxaliplatin delivers a powerful synergistic effect, effectively resensitizing resistant colorectal cancer cells both in vitro and in vivo. This combination strategy exploits the weakness created by the resistant cells' own dependency on autophagy.
In conclusion, our work moves beyond merely inhibiting a resistance mechanism. We present a paradigm-shifting strategy: hijacking the very pathway that confers resistance (autophagy) to trigger a potent alternative cell death (ferroptosis). This approach offers a promising and targeted therapeutic avenue to break the cycle of treatment failure in colorectal cancer and potentially other resistant malignancies.
