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

Deepak Vangala, Swetlana Ladigan, Sven T. Liffers, Soha Noseir, Abdelouahid Maghnouj, Tina Maria Götze, Berlinda Verdoodt, Susanne Klein-Scory, Laura Godfrey, Martina K. Zowada, Mario Huerta, Daniel L. Edelstein, Jaime Martinez de Villarreal, Miriam Marqués, Jörg Kumbrink, Andreas Jung, Tobias Schiergens, Jens Werner, Volker Heinemann, Sebastian StintzingDoris Lindoerfer, Ulrich Mansmann, Michael Pohl, Christian Teschendorf, Christiane Bernhardt, Heiner Wolters, Josef Stern, Selami Usta, Richard Viebahn, Jacob Admard, Nicolas Casadei, Stefan Fröhling, Claudia R. Ball, Jens T. Siveke, Hanno Glimm, Andrea Tannapfel, Wolff Schmiegel, Stephan A. Hahn

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Article number116
JournalGenome Medicine
Volume13
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

Keywords

  • Anti-EGFR
  • PDX
  • Secondary resistance
  • Targeted treatment
  • Transcriptional reprogramming

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