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.

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype / B. Lupo, F. Sassi, M. Pinnelli, F. Galimi, E.R. Zanella, V. Vurchio, G. Migliardi, P.A. Gagliardi, A. Puliafito, D. Manganaro, P. Luraghi, M. Kragh, M.W. Pedersen, I.D. Horak, C. Boccaccio, E. Medico, L. Primo, D. Nichol, I. Spiteri, T. Heide, A. Vatsiou, T.A. Graham, E. Elez, G. Argiles, P. Nuciforo, A. Sottoriva, R. Dienstmann, D. Pasini, E. Grassi, C. Isella, A. Bertotti, L. Trusolino. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 12:555(2020 Aug 05), pp. eAAX8313.1-eAAX8313.17. [10.1126/SCITRANSLMED.AAX8313]

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype

D. Pasini;
2020

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.
Settore BIO/11 - Biologia Molecolare
   The functional interaction of EGFR and beta-catenin signalling in colorectal cancer: Genetics, mechanisms, and therapeutic potential.
   BEAT
   European Commission
   Horizon 2020 Framework Programme
   724748

   Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions
   COLOSSUS
   European Commission
   Horizon 2020 Framework Programme
   754923

   EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts
   EDIReX
   European Commission
   Horizon 2020 Framework Programme
   731105
5-ago-2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
scitranslmed.aax8313.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.45 MB
Formato Adobe PDF
1.45 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Lupo_et_al_Science_Transl_Med_2020_compressed.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 5.84 MB
Formato Adobe PDF
5.84 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/946621
Citazioni
  • ???jsp.display-item.citation.pmc??? 21
  • Scopus 33
  • ???jsp.display-item.citation.isi??? 34
social impact