A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer

Abstract

Patient-derived xenograft models (PDX) are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathological features, mutational profiles, gene expression, and copy number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas (TCGA) and to previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected based on the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research.

Genomic evolution of non-small cell lung cancer patient-derived xenograft models

“…Here we have investigated the genomic evolution of NSCLC during subcutaneous engraftment and propagation in immunocompromised mice. Although a recent pan-cancer WES study found ~10% discordance in driver mutations in patient-PDX pairs, indicative of clonal evolution during engraftment 27 , previous studies based on gene expression profiling, SNP array, panel sequencing and/or whole-genome sequencing have demonstrated widespread conservation of the genomic landscape in PDX models from a range of cancer types 6,8,28 . However, these studies have been limited in their ability to detect subclonal events by a lack of patient tumour multi-region sampling.…”

“…For pre-clinical oncology applications, the fidelity of PDX models is of major importance. Across cancer types, including non-small cell lung cancer (NSCLC) 6 , PDX models bear histological similarity to the tumours from which they were derived. However, recent high-resolution analyses of breast cancer PDX models suggest that PDX models, like patient tumours, can comprise multiple genetically defined subclones 7 and that these undergo dynamic changes in their relative abundance during PDX engraftment and expansion 8 .…”

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

“…Exploring new treatment targets and testing new treatment strategies using appropriate in vivo models should be given high priority. For traditional animal models, it is impossible to simulate all subtypes of NSCLC, but PDXs can overcome this limitation, which recapitulate faithfully many aspects of the primary tumors histology, karyotype, and genomics, as well as expected sensitivity and resistance patterns to various treatment regimens observed in patients [35] .…”

Patient-derived xenograft models in cancer therapy: technologies and applications

“… 110 Besides the consortium-led PDX biobanks, many organizations provide PDX model platforms with genomic data. 111 When testing the function of novel drugs, researchers can pick out PDX models from the biobanks according to cancer types or molecular features (Table 3 ). As the PDX transplantation technologies become mature and the sequencing technologies accessible, researchers can tailor specialized PDX biobanks to capture the various molecular features of patients across different cancer stages, molecular subtypes, and anatomic sites.…”