2. Academic Validation
  3. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models

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

  • Genome Med. 2021 Jul 16;13(1):116. doi: 10.1186/s13073-021-00926-7.
Deepak Vangala  # 1 2,  Swetlana Ladigan  # 1 2,  Sven T Liffers 3 4,  Soha Noseir 1,  Abdelouahid Maghnouj 1,  Tina-Maria Götze 1,  Berlinda Verdoodt 3,  Susanne Klein-Scory 2,  Laura Godfrey 5 6,  Martina K Zowada 7 8,  Mario Huerta 7 9,  Daniel L Edelstein 10,  Jaime Martinez de Villarreal 11,  Miriam Marqués 11,  Jörg Kumbrink 12 13,  Andreas Jung 12 13,  Tobias Schiergens 14,  Jens Werner 14,  Volker Heinemann 15,  Sebastian Stintzing 16,  Doris Lindoerfer 17,  Ulrich Mansmann 17,  Michael Pohl 2,  Christian Teschendorf 18,  Christiane Bernhardt 18,  Heiner Wolters 19,  Josef Stern 19,  Selami Usta 19,  Richard Viebahn 20,  Jacob Admard 21,  Nicolas Casadei 21,  Stefan Fröhling 22 23,  Claudia R Ball 7 9 24 25,  Jens T Siveke 5 6,  Hanno Glimm 7 9 24 25,  Andrea Tannapfel 3,  Wolff Schmiegel 2,  Stephan A Hahn 26 27
Affiliations

Affiliations

  • 1 Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany.
  • 2 Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany.
  • 3 Institute of Pathology, Ruhr University of Bochum, Bochum, Germany.
  • 4 Present Address Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 5 Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 6 Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
  • 7 Translational Functional Cancer Genomics, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 8 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 9 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), Dresden, and German Cancer Research Center (DKFZ), Dresden, Germany.
  • 10 Medical Scientific Affairs, Sysmex Inostics Inc., Baltimore, MD, USA.
  • 11 Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) and CIBERONC, Madrid, Spain.
  • 12 Institute of Pathology, Ludwig Maximilian University (LMU), Munich, Germany.
  • 13 German Cancer Consortium (DKTK, partner site Munich), Munich, Germany.
  • 14 Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany.
  • 15 Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
  • 16 Department of Hematology, Oncology, and Tumor Immunology (CCM) Charité Universitaetsmedizin Berlin, Berlin, Germany.
  • 17 Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 18 Department of Internal Medicine, St. Josefs-Hospital, Dortmund, Germany.
  • 19 Department of Visceral and General Surgery, St. Josef Hospital, Dortmund, Germany.
  • 20 Department of Surgery, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany.
  • 21 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • 22 German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 23 Deptartment of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center, Heidelberg, Germany.
  • 24 Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany.
  • 25 German Cancer Consortium (DKTK), Dresden, Germany.
  • 26 Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany. [email protected].
  • 27 Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus, Bochum, Germany. [email protected].
  • # Contributed equally.
PMID: 34271981 DOI: 10.1186/s13073-021-00926-7
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.

Keywords

Anti-EGFR; PDX; Secondary resistance; Targeted treatment; Transcriptional reprogramming.

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