Validity of patient-derived xenograft mouse models for lung cancer based on exome sequencing data.

Jaewon Kim,Sanghyuk Lee,Jhingook Kim,Hwanseok Rhee

doi:10.5808/gi.2020.18.1.e3

Jaewon Kim, Sanghyuk Lee + Show 2 more

Open Access

https://doi.org/10.5808/gi.2020.18.1.e3

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Abstract

Patient-derived xenograft (PDX) mouse models are frequently used to test the drug efficacy in diverse types of cancer. They are known to recapitulate the patient characteristics faithfully, but a systematic survey with a large number of cases is yet missing in lung cancer. Here we report the comparison of genomic characters between mouse and patient tumor tissues in lung cancer based on exome sequencing data. We established PDX mouse models for 132 lung cancer patients and performed whole exome sequencing for trio samples of tumor-normal-xenograft tissues. Then we computed the somatic mutations and copy number variations, which were used to compare the PDX and patient tumor tissues. Genomic and histological conclusions for validity of PDX models agreed in most cases, but we observed eight (~7%) discordant cases. We further examined the changes in mutations and copy number alterations in PDX model production and passage processes, which highlighted the clonal evolution in PDX mouse models. Our study shows that the genomic characterization plays complementary roles to the histological examination in cancer studies utilizing PDX mouse models.

Highlights

Lung cancer incidence and mortality rates are the highest worldwide, accounting for 11.6% of the total cases and 18.4% of the total cancer deaths in 2018 [1]
Traditional treatment for lung cancer has been surgery and radiochemotherapy, but targeted therapies are increasingly adopted for patients who have the druggable aberrations such as epidermal growth factor receptor (EGFR) mutations or gene fusions involving ALK, ROS1, and NTRK genes [2,3,4,5]
In accordance with the previous reports [19], the success rate of establishing Patient-derived xenograft (PDX) mouse models was higher in squamous cell carcinoma than in adenocarcinoma

Summary

Introduction

Lung cancer incidence and mortality rates are the highest worldwide, accounting for 11.6% of the total cases and 18.4% of the total cancer deaths in 2018 [1]. Traditional treatment for lung cancer has been surgery and radiochemotherapy, but targeted therapies are increasingly adopted for patients who have the druggable aberrations such as epidermal growth factor receptor (EGFR) mutations or gene fusions involving ALK, ROS1, and NTRK genes [2,3,4,5]. Targeted therapies usually show fast response with minimal side effects, but tumor recurs within a few months in many cases, necessitating additional therapies. The main reasons for resistant and recurrent tumors are intrinsic heterogeneity and tumor cell evolution. Tumors may consist of multiple clones where targeted therapies kill only subsets of clones leaving residual clones, whose proliferation leads to resistance or recurrence eventually. Tumor cells may undergo evolution after treatment to acquire de novo mutations overcoming the treatment effect of cancer drugs.

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