TY - JOUR
T1 - Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell-like phenotype
AU - Lupo, Barbara
AU - Sassi, Francesco
AU - Pinnelli, Marika
AU - Galimi, Francesco
AU - Zanella, Eugenia R
AU - Vurchio, Valentina
AU - Migliardi, Giorgia
AU - Gagliardi, Paolo Armando
AU - Puliafito, Alberto
AU - Manganaro, Daria
AU - Luraghi, Paolo
AU - Kragh, Michael
AU - Pedersen, Mikkel W
AU - Horak, Ivan D
AU - Boccaccio, Carla
AU - Medico, Enzo
AU - Primo, Luca
AU - Nichol, Daniel
AU - Spiteri, Inmaculada
AU - Heide, Timon
AU - Vatsiou, Alexandra
AU - Graham, Trevor A
AU - Élez, Elena
AU - Argiles, Guillem
AU - Nuciforo, Paolo
AU - Sottoriva, Andrea
AU - Dienstmann, Rodrigo
AU - Pasini, Diego
AU - Grassi, Elena
AU - Isella, Claudio
AU - Bertotti, Andrea
AU - Trusolino, Livio
N1 - Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2020/8/5
Y1 - 2020/8/5
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.aax8313
DO - 10.1126/scitranslmed.aax8313
M3 - Article
C2 - 32759276
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 555
ER -