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

Abstract

ABSTRACTPatient-derived xenograft (PDX) models of cancer, developed through injection of patient tumour cells into immunocompromised mice, have been widely adopted in preclinical studies, as well as in precision oncology approaches. However, the extent to which PDX models represent the underlying genetic diversity of a patient’s tumour and the extent of on-going genomic evolution in PDX models are incompletely understood, particularly in the context of heterogeneous cancers such as non-small cell lung cancer (NSCLC). To investigate the depiction of intratumour heterogeneity by PDX models, we derived 47 new subcutaneous multi-region PDX models from 22 patients with primary NSCLC enrolled in the clinical longitudinal cohort study TRACERx. By analysing whole exome sequencing data from primary tumours and PDX models, we find that PDX establishment creates a genomic bottleneck, with 76% of PDX models being derived from a single primary tumour subclone. Despite this, multiple primary tumour subclones were capable of PDX establishment in regional PDX models, indicating that PDX libraries derived from multiple tumour regions can capture intratumour heterogeneity. Acquisition of somatic mutations continued during PDX model expansion, and was associated with APOBEC- or mismatch repair deficiency-induced mutational signatures in a subset of models. Overall, while NSCLC PDX models retain truncal genomic alterations, the absence of subclonal heterogeneity representative of the primary tumour is a major limitation. Our results emphasise the importance of characterising and monitoring intratumour heterogeneity in the context of pre-clinical cancer studies.