Utility of patient-derived xenografts to evaluate drug sensitivity and select optimal treatments for individual non-small-cell lung cancer patients

Xiaoqing Wang ¹, Ju Zhu ², Lingling Li ¹

⁰Pharmacogenetics and Pharmacogenomics Laboratory, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.

Molecular Medicine +

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November 11, 2024

View abstract on PubMed

Summary

Patient-derived xenografts (PDXs) accurately model patient tumors for drug testing. A novel PDX model identified a DUSP6 mutation causing Osimertinib resistance, treatable with Trametininib.

Area Of Science

Oncology
Preclinical Research
Genomics

Background

Patient-derived xenografts (PDXs) are crucial preclinical models for evaluating drug sensitivity and resistance.
They aid in selecting individualized treatment regimens for cancer patients.

Purpose Of The Study

To establish and characterize Non-Small Cell Lung Cancer (NSCLC) PDX models.
To investigate mechanisms of acquired resistance to Osimertinib.
To identify alternative treatment strategies for Osimertinib-resistant NSCLC.

Main Methods

Histopathological examination, immunohistochemistry, and whole-exome sequencing (WES) were used to confirm PDX similarity to primary tumors.
In vivo drug reactivity was validated.
WES and Western Blot (WB) were employed to investigate Osimertinib resistance mechanisms.

Main Results

13 NSCLC-PDXs were successfully established from 62 patients.
PDX treatment responses mirrored patient responses to conventional chemotherapy.
A DUSP6 M62I mutation leading to MAPK-ERK pathway overactivation was identified as a cause of Osimertinib resistance.
Trametinib effectively inhibited tumor growth in Osimertinib-resistant PDX models.

Conclusions

NSCLC PDX models accurately reflect patient tumor characteristics and drug responses.
The DUSP6 M62I mutation-driven MAPK-ERK pathway activation is a key mechanism of Osimertinib resistance.
Targeting the MAPK-ERK pathway with Trametinib offers a promising alternative treatment for Osimertinib-resistant NSCLC patients.

Keywords:

Drug sensitivity Individualized chemotherapy regimen Non-small-cell lung cancer Osimertinib resistance Patient-derived xenografts