2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12A.06 Diarylheptanoid 35d Overcomes EGFR TKI Resistance by Inducing EGFR Degradation in EGFR-Mutant Lung Adenocarcinoma

EP.12A.06 Diarylheptanoid 35d Overcomes EGFR TKI Resistance by Inducing EGFR Degradation in EGFR-Mutant Lung Adenocarcinoma

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Diarylheptanoid 35d has been identified as a promising therapeutic agent to overcome EGFR TKI (tyrosine kinase inhibitor) resistance in EGFR-mutant lung adenocarcinoma, a common issue faced by patients with this type of cancer. Typically, patients initially respond well to EGFR TKIs, such as Osimertinib, but eventually develop resistance due to a switch in EGFR downstream signaling from TKI-sensitive to TKI-insensitive pathways.<br /><br />In this study led by Dr. Xuan Hong from Harbin Medical University Cancer Hospital, diarylheptanoid 35d, a derivative of curcumin, was developed and screened among other compounds for its ability to reduce EGFR expression. The research involved both in vitro and in vivo tests on multiple TKI-resistant lung adenocarcinoma models. The results indicated that 35d effectively suppressed EGFR protein expression and inhibited tumor growth, even in the presence of challenging mutations like EGFR C797S. The combination of 35d with Osimertinib significantly prevented tumor progression and increased survival rates in mice without negatively affecting liver and kidney functions or body weight.<br /><br />Mechanistically, 35d induces EGFR degradation through the hsp70-mediated lysosomal pathway, aided by the transcriptional activation of various components such as HSPA1B. This discovery positions 35d as a potential new therapeutic agent that could be further developed to address the urgent unmet need for effective treatments against TKI-resistant EGFR-mutant lung adenocarcinomas.<br /><br />This research was supported by various funds, including the China Medical University YingTsai Young Scholar Award and the National Natural Science Foundation of China, among others. The successful outcomes from this study could contribute significantly to the development of new treatments for lung cancer patients facing drug resistance.

Asset Subtitle

Xuan Hong

Meta Tag

Speaker Xuan Hong

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

diarylheptanoid 35d

EGFR TKI resistance

lung adenocarcinoma

Osimertinib

EGFR C797S mutation

hsp70-mediated lysosomal pathway

curcumin derivative

tumor growth inhibition

EGFR degradation

TKI-resistant treatments