Breakthrough Method Tackles Cancer Drug Resistance

Abstract

Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non-lysosome-targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion-mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti-tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy.

A research team, affiliated with UNIST has unveiled an innovative technology to eliminate drug-resistant cancer cells using light. Professors Tae-Hyuk Kwon and Duyoung Min from the Department of Chemistry at UNIST, alongside Professor Taiho Park from POSTECH, have created a photoreactive compound capable of suppressing autophagy in cancer cells-one of the key mechanisms contributing to resistance against anticancer therapies.

Cancer cells are known for their remarkable adaptability, posing significant challenges in the development of effective treatments. One of their survival strategies is autophagy, a process in which cells degrade and recycle waste products. This mechanism not only allows cancer cells to expel anticancer drugs but also provides them with energy by repurposing the waste materials, thereby evading immune detection.

To combat this autophagy, the research team designed a photoreactive compound that integrates morpholine and iridium. Morpholine selectively targets cell lysosomes, the organelles where autophagy occurs, while iridium activates upon exposure to light to induce oxidative damage.

In preclinical studies, when this photoreactive compound was administered to mice with drug-resistant pancreatic cancer and subsequently exposed to infrared light, the results were striking. The resistant pancreatic cancer tissues diminished significantly, with complete tumor eradication observed within just seven days.

Analysis revealed that the compound, upon light activation, disrupted the lysosomal membrane and prevented its fusion with autophagosomes-structures responsible for isolating cellular waste. The research team noted that they plan to investigate additional proteins involved in this oxidative damage process.

Mingyu Park from the Department of Chemistry served as the lead researcher on this study, with O2Medi Co., Ltd. conducting assessments of toxicity and anticancer efficacy using an animal model.

Professor Kwon remarked, "This groundbreaking approach to targeting autophagy could significantly enhance treatment options for major intractable cancers that exhibit drug resistance." He added, "We are also exploring the efficacy of combination therapies that incorporate existing anticancer agents alongside gemcitabine."

Their findings have been published in the Advanced Science on January 13, 2025. This study has been supported by the National Research Foundation of Korea (NRF), the National Cancer Center (NCC), the Korea Technology and information Promotion Agency for SMEs, the Korea Innovation Foundation, and UNIST.

Journal Reference

Mingyu Park, Jung Seung Nam, Taehyun Kim, et al., "Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug-Resistant Cancer via Oxidative Autophagy Inhibition," Adv. Sci., (2025).