Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models

Genome Medicine

Laura Godfrey¹  Jens T. Siveke¹  Jens Werner²  Tobias Schiergens²  Sebastian Stintzing³  Wolff Schmiegel⁴  Susanne Klein-Scory⁴  Michael Pohl⁴  Christian Teschendorf⁵  Christiane Bernhardt⁵  Volker Heinemann⁶  Soha Noseir⁷  Abdelouahid Maghnouj⁷  Tina-Maria Götze⁷  Stephan A. Hahn⁸  Swetlana Ladigan⁸  Deepak Vangala⁸  Richard Viebahn⁹  Josef Stern^1,10  Selami Usta^1,10  Heiner Wolters^1,10  Miriam Marqués^1,11  Jaime Martinez de Villarreal^1,11  Stefan Fröhling^1,12  Doris Lindoerfer^1,13  Ulrich Mansmann^1,13  Nicolas Casadei^1,14  Jacob Admard^1,14  Jörg Kumbrink^1,15  Andreas Jung^1,15  Andrea Tannapfel^1,16  Berlinda Verdoodt^1,16  Sven T. Liffers^1,17  Daniel L. Edelstein^1,18  Mario Huerta^1,19  Hanno Glimm^2,20  Claudia R. Ball^2,20  Martina K. Zowada^2,21 

[1] Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany;Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany;Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany;Department of Hematology, Oncology, and Tumor Immunology (CCM) Charité Universitaetsmedizin Berlin, Berlin, Germany;Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany;Department of Internal Medicine, St. Josefs-Hospital, Dortmund, Germany;Department of Medicine III, University Hospital, LMU Munich, Munich, Germany;Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany;Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany;Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany;Department of Surgery, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany;Department of Visceral and General Surgery, St. Josef Hospital, Dortmund, Germany;Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC, Madrid, Spain;German Cancer Consortium (DKTK), Heidelberg, Germany;Deptartment of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center, Heidelberg, Germany;Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;Institute of Pathology, Ludwig Maximilian University (LMU), Munich, Germany;German Cancer Consortium (DKTK, partner site Munich), Munich, Germany;Institute of Pathology, Ruhr University of Bochum, Bochum, Germany;Institute of Pathology, Ruhr University of Bochum, Bochum, Germany;Present Address Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany;Medical Scientific Affairs, Sysmex Inostics Inc., Baltimore, MD, USA;Translational Functional Cancer Genomics, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), Dresden, and German Cancer Research Center (DKFZ), Dresden, Germany;Translational Functional Cancer Genomics, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), Dresden, and German Cancer Research Center (DKFZ), Dresden, Germany;Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany;German Cancer Consortium (DKTK), Dresden, Germany;Translational Functional Cancer Genomics, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany;Faculty of Biosciences, Heidelberg University, Heidelberg, Germany;

关键词: Anti-EGFR;    PDX;    Secondary resistance;    Targeted treatment;    Transcriptional reprogramming;   

DOI  :  10.1186/s13073-021-00926-7

来源: Springer

【 摘 要 】

BackgroundThe development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms.MethodsWe analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.ResultsIn vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies.ConclusionsOur study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.

【 授权许可】

CC BY