Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype
- 5 August 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (555)
- https://doi.org/10.1126/scitranslmed.aax8313
Abstract
Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease.Keywords
Funding Information
- European Research Council (ERC Consolidator Grant 724748 - BEAT)
- Associazione Italiana per la Ricerca sul Cancro (20697)
- Associazione Italiana per la Ricerca sul Cancro (12944)
- Associazione Italiana per la Ricerca sul Cancro (18532)
- Associazione Italiana per la Ricerca sul Cancro (21091)
- Associazione Italiana per la Ricerca sul Cancro (AIRC/CRUK/FC AECC Accelerator Award 22795)
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5x1000 Ministero della Salute 2010)
- Associazione Italiana per la Ricerca sul Cancro (19047)
- H2020 INFRAIA (731105 - EDIReX)
- Associazione Italiana per la Ricerca sul Cancro (21091)
- ERAnet Transcan (TACTIC)
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5x1000 Ministero della Salute 2014)
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5x1000 Ministero della Salute 2015)
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5x1000 Ministero della Salute 2016)
- European Union H2020 programme (754923)
- Associazione Italiana per la Ricerca sul Cancro (IG-2017-20290)
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