ENA 2024 Poster 275

Osimertinib-Resistant NSCLC Patient-Derived Xenograft Model Mimics Clinical Response Status of Multiple TKI Treatments in Preclinical Study

Jinxi Wang, Qingzhi Liu, Leilei Chen, Jiawen Gao, Jun Zhou, Likun Zhang, Wubin Qian, Rongfei Lu, Ludovic Bourre, Jessie J.J. Wang

EGFR mutations are found in 10–15% of Caucasian and 30–40% of Asian patients with non-small cell lung cancer (NSCLC). Early-generation EGFR-targeted tyrosine kinase inhibitors (TKIs) showed significant efficacy in treating patients with EGFR mutations, such as exon 19 deletion and L858R. However, resistance often develops due to secondary mutations, notably EGFR T790M, which blocks the binding of first- and second-generation TKIs to the ATP-binding site of EGFR.

While the third-generation irreversible EGFR TKI, Osimertinib, effectively overcomes T790M-mediated resistance, further resistance frequently arises. This study introduces a new PDX model derived from a pretreated patient that recapitulates the resistance found in the clinic. The paired organoid model further supports efficient in vitro screening, enhancing the overall strategy for addressing resistance issues.

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• How pretreated PDX models can recapitulate the same resistant phenotype observed in the clinic.
• How pretreated PDX models can be used to study resistance mechanisms as well as novel approaches to overcome said resistance.
• Matched organoid models that can be used for in vitro screenings or mechanism of action studies.

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