Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors

Abstract

Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient‐derived tumor xenograft (PDX) resource from surgically resected non‐small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non‐obese severe combined immune deficient (NOD SCID) gamma mice. Subsequent passages were in NOD SCID mice. A subset of matched patient and PDX tumors and non‐neoplastic lung tissues were profiled by whole exome sequencing, single nucleotide polymorphism (SNP) and methylation arrays, and phosphotyrosine (pY)‐proteome by mass spectrometry. The data were compared to published NSCLC datasets of NSCLC primary and cell lines. 127 stable PDXs were established from 441 lung carcinomas representing all major histological subtypes: 52 adenocarcinomas, 62 squamous cell carcinomas, one adeno‐squamous carcinoma, five sarcomatoid carcinomas, five large cell neuroendocrine carcinomas, and two small cell lung cancers. Somatic mutations, gene copy number and expression profiles, and pY‐proteome landscape of 36 PDXs showed greater similarity with patient tumors than with established cell lines. Novel somatic mutations on cancer associated genes were identified but only in PDXs, likely due to selective clonal growth in the PDXs that allows detection of these low allelic frequency mutations. The results provide the strongest evidence yet that PDXs established from lung cancers closely mimic the characteristics of patient primary tumors.

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

“…Because patient-derived xenografts (PDX) closely mimic the molecular characteristics and heterogeneity of the original patient tumors, we further tested four cell lines cultured from early passage PDXs (PDX239, PDX277, PDX462 and PDX267) (24). Nine of the eleven cell lines achieved combination indices < 1.0, consistent with a synergistic response at nanomolar drug concentrations (Figure 1B; Supplemental Table S4).…”

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

“…Evidence has shown that PDXs retain the genome-wide exomic nucleotide variants, gene copy number alterations, and DNA methylation patterns of their corresponding tumors [1][2][3][4] irrespective of the number of passages, 1,3 although clonal selection during initial engraftment and passaging of PDXs has been observed. They have been shown to recapitulate the histologic and genetic features of human primary tumors and to be useful in assessing treatment response.…”

Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft

“…Although to our knowledge no such studies have been previously performed in the field of pediatric oncology, the low recapitulation of the proteomic landscape when MBLX was compared to primary MBL tumors is inconsistent with omics studies comparing xenografts of breast and colon cancers to their corresponding patient tumors (13,14). Our data, are in line with data derived from cell lines, that in previous comparisons to patient tumors have shown low correlation rates between their point-mutation frequencies, and marked differences in their mRNA and copy number profiles (15,16).…”