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

Genome Medicine

Jens T. Siveke¹  Laura Godfrey¹  Jens Werner²  Tobias Schiergens²  Sebastian Stintzing³  Wolff Schmiegel⁴  Michael Pohl⁴  Susanne Klein-Scory⁴  Christian Teschendorf⁵  Christiane Bernhardt⁵  Volker Heinemann⁶  Abdelouahid Maghnouj⁷  Stephan A. Hahn⁷  Soha Noseir⁷  Swetlana Ladigan⁷  Deepak Vangala⁷  Tina-Maria Götze⁷  Richard Viebahn⁸  Heiner Wolters⁹  Josef Stern⁹  Selami Usta⁹  Miriam Marqués^1,10  Jaime Martinez de Villarreal^1,10  Stefan Fröhling^1,11  Doris Lindoerfer^1,12  Ulrich Mansmann^1,12  Jacob Admard^1,13  Nicolas Casadei^1,13  Jörg Kumbrink^1,14  Andreas Jung^1,14  Andrea Tannapfel^1,15  Sven T. Liffers^1,15  Berlinda Verdoodt^1,15  Daniel L. Edelstein^1,16  Hanno Glimm^1,17  Martina K. Zowada^1,17  Mario Huerta^1,17  Claudia R. Ball^1,17 

[1] Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen;Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich;Department of Hematology, Oncology, and Tumor Immunology (CCM) Charité Universitaetsmedizin Berlin;Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus;Department of Internal Medicine, St. Josefs-Hospital;Department of Medicine III, University Hospital, LMU Munich;Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum;Department of Surgery, Ruhr University Bochum, Knappschaftskrankenhaus;Department of Visceral and General Surgery, St. Josef Hospital;Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC;German Cancer Consortium (DKTK);Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München;Institute of Medical Genetics and Applied Genomics, University of Tübingen;Institute of Pathology, Ludwig Maximilian University (LMU);Institute of Pathology, Ruhr University of Bochum;Medical Scientific Affairs, Sysmex Inostics Inc.;Translational Functional Cancer Genomics, NCT Heidelberg and German Cancer Research Center (DKFZ);

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

DOI  :  10.1186/s13073-021-00926-7

来源: DOAJ

【 摘 要 】

Abstract Background The 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. Methods We 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. Results In 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. Conclusions Our 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】

Unknown