3MO - Genomic evolution of non-small cell lung cancer during the establishment and propagation of patient-derived xenograft models

Background

Patient-derived xenograft (PDX) models are a key tool in the pre-clinical oncology pipeline as a result of their in vivo propagation and proximity to patient material. The extent to which PDX models capture patient heterogeneity is therefore important for applications in pre-clinical and co-clinical studies. To improve our understanding of genomic selection and evolution in PDX models, we derived multiple PDX models from patients enrolled in TRACERx – a study of the evolutionary dynamics of non-small cell lung cancer (NSCLC) that uses a multi-region deep whole-exome sequencing (WES) approach.

Methods

We transplanted regional NSCLC tumor tissue subcutaneously into immunocompromised NSG mice. PDX models and matched patient tumor regions were subjected to WES.

Results

145 regional tumor samples from 44 patients were attempted, resulting in 63 xenografts. Of these, 47 regional xenografts were NSCLC-derived, while 16 were B-cell lymphoproliferative disease. Cryopreservation of tumor samples prior to injection did not alter PDX take rates. Histologically, broad similarity was observed between PDX models and corresponding patient tumor regions. Analysis of WES data revealed that PDX models are frequently monoclonal, but retain genomic similarity to the region of origin compared to spatially distinct tumor regions. On-going evolution occurs within PDX models but contributes less to genomic divergence than initial bottlenecking events. Specific mutational signatures can define the evolutionary trajectories of individual PDX models.

Conclusions

Overall, this study demonstrates that spatially defined PDX model libraries can be developed by multiple sampling of primary tumors. This approach may improve PDX take rates for individual patients and help to generate PDX model collections that represent the intratumor diversity of NSCLC.

Legal entity responsible for the study

University College London.

Funding

Cancer Research UK; Wellcome Trust; The Roy Castle Lung Cancer Foundation; The James Tudor Foundation.

Disclosure

R. Hynds: Financial Interests, Personal, Stocks/Shares: Achilles Therapeutics. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited Speaker Honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.