Abstract A102: Molecular profiling of a non-small cell lung PDX collection by whole exome sequencing and RNAseq revealed subtype specificities with therapeutic implications
Authors: Peille Anne-Lise , Zeitouni Bruno , Fiebig Vanina , Fiebig Heinz-Herbert , Vuaroqueaux Vincent 
Published: May 2016

Non-small cell lung cancer (NSCLC) is a heterogeneous disease comprising different histological subtypes with therapeutic implications. We have established a collection of 76 NSCLC patient-derived xenografts (PDX) comprising adenocarcinoma (39), squamous cell carcinoma (24) and large-cell carcinoma (11) models (2 mixed) for use in anti-cancer drug development and pharmacogenomics research. We analyzed the molecular diversity of our PDX collection using whole-exome sequencing, Affymetrix SNP6.0 and RNAseq, assessed their similarity to patient tumors and the impact on drug testing.

Similar to patient lung cancers, genomic analyses revealed that the NSCLC PDX were heavily altered tumors with an overall mutations load ranking from 317 to 1549 per model (mean = 682 mutations). We retrieved signatures of mutational processes known to be associated with ageing, smoking and APOBEC alterations. In addition to the mutations, chromosomal instability characterized by polyploidy including focal gene amplifications (most frequently 2p11.2, 14q32.33) and deletions (e.g. recurrent deletions of 3p14.2, 9p21.3) and gene fusions were detected. While no significant differences in average mutation loads or levels of polyploidy between the histotypes were found, histotype-specific gene alterations and gene expression profiles were identified.

In line with in vivo resistance to anti-EGFR treatment, alterations of the RAS/RAF pathway, PIK3CA and PTEN, as well as the MET amplification occurred more frequently in adenocarcinoma and large cell PDX explaining the resistance of 90% of models to anti-EGFR. Among adenocarcinoma and large cell PDX, we identified three models with EGFR mutations, one of which contained the codon insertion EGFRM766X associated with a strong sensitivity towards cetuximab but not erlotinib.

In addition, we identified adenocarcinoma PDX models in which KIT was amplified and large cell PDX with deletions in CDKN2A/B, alterations in the RAS/RAF pathway (73%) and epigenetic regulation pathways (64%). Squamous cell PDX were less frequently altered in the RAS/RAF pathway, but frequently had altered TP53 (90%), PIK3CA and PTEN (30%) and high expression of TP63 and FGFR3. Furthermore, a highly expressed FGFR3-TACC3 fusion gene was identified in one squamous cell PDX, which is under evaluation for sensitivity towards anti-FGFR3. Regarding PDX response to standard-of-care agents, squamous cell PDX were the most sensitive to cisplatin whereas adenocarcinoma PDX were the most resistant (p = 0.003). In contrast, both groups were more sensitive to paclitaxel than large cell PDX (p = 0.03). These findings suggest distinct molecular profiles influence the response to cytotoxic agents.

Molecular profiling of our NSCLC PDX collection confirmed its similarity to patient tumors and highlighted the distinct molecular specificities of each subtype, suggesting different therapeutic approaches. This extensive characterization will help improve the selection of PDX models in future drug development.

Citation Format: Anne-Lise Peille, Bruno Zeitouni, Vanina Fiebig, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. Molecular profiling of a non-small cell lung PDX collection by whole exome sequencing and RNAseq revealed subtype specificities with therapeutic implications. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A102.