△ Schematic illustration of the synergistic anticancer mechanism of the alpelisib–chloroquine combination therapy through PI3K pathway inhibition and autophagy blockade

A joint research team led by Professor Ji-Yoon Kim from the Department of Pharmacology, College of Medicine, The Catholic University of Korea, has proposed a new therapeutic strategy to overcome drug resistance—a major limitation of targeted therapies for lung cancer.

The team included Research Professor Jin-Young Kim and Ph.D. candidate Chandani Shrestha (co–first authors), Professor Byoung-Yong Shim (Department of Oncology, St. Vincent’s Hospital), and Professor Dong-Woo Chae (Department of Pharmacology, Yonsei University College of Medicine) as co–corresponding authors. Together, they developed a combination therapy that enhances the efficacy of existing targeted anticancer drugs by inhibiting autophagy, a process by which cancer cells degrade and recycle damaged components to survive.

Non–small cell lung cancer (NSCLC), which accounts for about 85% of lung cancers, remains one of the leading causes of cancer deaths worldwide. Although targeted therapies have changed the treatment paradigm, the emergence of drug resistance during treatment remains a critical challenge.

The research team focused on alpelisib, a targeted therapy used for lung cancer patients with PI3K mutations (Phosphoinositide 3-kinase, a signaling gene involved in cancer cell growth and survival). While alpelisib blocks tumor growth signals, cancer cells evade the drug by activating autophagy as a survival mechanism—essentially “cleaning themselves up” to withstand treatment.

To dismantle this defense mechanism, the researchers combined alpelisib with chloroquine, an existing autophagy inhibitor long used as an antimalarial drug with proven safety. In both in vitro and in vivo studies, the combination therapy significantly increased cancer cell apoptosis (programmed cell death) and strongly suppressed tumor growth and metastasis compared to single-drug treatments.

The core of this research lies in its strategic approach—analyzing cancer survival in terms of “attack and defense.” While alpelisib acts as an attacker blocking growth pathways, autophagy functions as a shield protecting cancer cells. The team’s dual-targeting strategy disables the shield (autophagy) with chloroquine before delivering the decisive attack with alpelisib. This approach not only enhances therapeutic effects in PI3K-mutant NSCLC but also shows potential for application in other resistant cancers.

This study also exemplifies drug repurposing—finding new uses for existing, clinically approved drugs—which accelerates clinical application by bypassing early safety verification steps. Since chloroquine has a long-established safety record, it offers a lower barrier for clinical trials and faster translation to patient treatment. The combination therapy showed particularly strong effects in patients with PIK3CA mutations, underscoring the value of precision medicine based on genetic profiles.

Building on these preclinical results, the team plans to conduct clinical trials of the alpelisib–chloroquine combination for NSCLC patients with PI3K mutations. They aim to evaluate its safety and efficacy while identifying biomarkers that can predict therapeutic responses—key tools for tailoring personalized cancer treatments.

Professor Kim stated, “If conventional targeted drugs act as attackers blocking cancer growth pathways, autophagy has been the cancer’s strongest defense. Our study demonstrates that chloroquine effectively removes this shield, allowing anticancer drugs to attack more efficiently.” She added, “Since both drugs are already proven safe in clinical settings, we hope this combination will bring new hope to lung cancer patients.”

This research holds significant implications for elucidating the root causes of targeted therapy resistance and expanding the therapeutic potential of existing drugs. The strategy of simultaneously targeting anticancer signaling and autophagy represents a refined understanding of the complex survival mechanisms of cancer cells.

The study was published in the international journal Biomedicine & Pharmacotherapy (IF 7.5, top 5.3% in pharmacology) and was supported by the National Research Foundation of Korea (Basic Research Laboratory and Mid-Career Researcher Support Programs) and Yuhan Corporation.

△ Prof. Ji-Yoon Kim, Prof. Jin-Young Kim, Ph.D. Candidate Chandani Shrestha, Prof. Byoung-Yong Shim, and Prof. Dong-Woo Chae