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

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. HeideA. Vatsiou, T.A. Graham, E. Élez, G. Argiles, P. Nuciforo, A. Sottoriva, R. Dienstmann, D. Pasini, E. Grassi, C. Isella, A. Bertotti, L. Trusolino

Research output: Contribution to journalArticlepeer-review


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. Copyright © 2020 The Authors, some rights reserved.
Original languageEnglish
JournalSci. Transl. Med.
Issue number555
Publication statusPublished - 2020


  • 4 (2 aminoethylamino) 1,8 dimethylimidazo[1,2 a]quinoxaline
  • 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one
  • alpelisib
  • buparlisib
  • cetuximab
  • dactolisib
  • epidermal growth factor receptor
  • epidermal growth factor receptor 2
  • epidermal growth factor receptor 3
  • everolimus
  • n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide
  • phosphatidylinositol 3 kinase
  • pictilisib
  • ruxolitinib
  • selumetinib
  • transcription factor Yap1
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • cell proliferation
  • cell subpopulation
  • cell survival
  • clinical effectiveness
  • colorectal cancer
  • controlled study
  • drug effect
  • drug efficacy
  • drug mechanism
  • drug response
  • female
  • human
  • human cell
  • intestine epithelium
  • male
  • minimal residual disease
  • mouse
  • NOD SCID mouse
  • nonhuman
  • Paneth cell
  • phenotype
  • priority journal
  • protein expression
  • protein targeting
  • signal transduction
  • treatment outcome
  • tumor volume


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