What question did this study set out to answer?

This research aims to assess how cannabidiol can enhance the effectiveness of etoposide against non-small cell lung cancer.

April 5, 2026

Abstract 4474: Cannabidiol enhances etoposide efficacy in non-small cell lung cancer by engaging a p53-mTOR-TFEB lysosomal death program.

Key Points

This research aims to assess how cannabidiol can enhance the effectiveness of etoposide against non-small cell lung cancer.
Tested several chemotherapeutics alongside cannabidiol in non-small cell lung cancer cells.
Conducted transcriptomic and proteomic analysis to evaluate gene expression changes.
Administered pharmacological blockade with PPARγ and GPR55 antagonists to analyze CBD response pathways.
Etoposide with cannabidiol significantly reduced NSCLC cell viability, showing a strong synergistic effect.
The combination led to increased autophagic cell death and downregulation of key oncogenes.
Impairment of the PI3K-AKT-mTOR pathway and reduction of TFEB phosphorylation were observed, enhancing lysosome-related gene expression.

Abstract

Abstract The search for more effective and safer cancer therapies has intensified interest in combination regimens that repurpose well-established agents. Here, we investigated whether cannabidiol (CBD), a cannabis-derived compound clinically used for pediatric epilepsy, can potentiate the anticancer activity of etoposide in non-small cell lung cancer (NSCLC). Among multiple chemotherapeutics tested, etoposide displayed the most pronounced reduction in NSCLC cell viability when combined with CBD, indicating a robust synergistic interaction. To elucidate the underlying mechanisms, we performed comprehensive transcriptomic and proteomic profiling, revealing that the CBD-etoposide combination up-regulated gene programs associated with autophagic cell death while concomitantly downregulating key oncogenic drivers linked to tumor progression. Mechanistically, this autophagic cell death was associated with PI3K-AKT-mTOR pathway inactivation and required functional p53. Importantly, downstream of mTOR suppression, the combination was associated with reduced TFEB phosphorylation, enhanced TFEB nuclear translocation, and increased transcriptional activation of lysosome-related gene networks, consistent with amplification of lysosomal stress programs that can contribute to lysosome-associated cell death. Notably, the therapeutic synergy was independent of classical cannabinoid receptors and transient receptor potential channels, supporting a noncanonical mode of CBD action. We also performed pharmacological blockade experiments using antagonists of PPARγ and GPR55 to test whether these pathways contribute to the CBD-etoposide response. Collectively, our findings suggest that CBD combined with etoposide represents a promising strategy to enhance treatment efficacy in NSCLC—particularly in tumors retaining p53 function—by concurrently engaging autophagic/lysosomal cell death programs and suppressing oncogenic signaling beyond canonical cannabinoid pathways. Citation Format: Youngsic Jeon, Hyukjoon Kwon, Young Nyun Park, Taejung Kim, Young-Joo Kim. Cannabidiol enhances etoposide efficacy in non-small cell lung cancer by engaging a p53-mTOR-TFEB lysosomal death program abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4474.

AIに質問

Bookmark