Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers

Sandra Misale, Ivana Bozic, Jingshan Tong, Ashley Peraza-Penton, Alice Lallo, Federica Baldi, Kevin H. Lin, Mauro Truini, Livio Trusolino, Andrea Bertotti, Federica Di Nicolantonio, Martin A. Nowak, Lin Zhang, Kris C. Wood, Alberto Bardelli

Research output: Contribution to journalArticle

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Abstract

Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

Original languageEnglish
Article number8305
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Sep 22 2015

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Mitogen-Activated Protein Kinase Kinases
Colorectal Neoplasms
cancer
retarding
therapy
Therapeutics
Heterografts
Pharmaceutical Preparations
drugs
actuators
Tumors
Drug Combinations
Chemical activation
Apoptosis
Neoplasms
Down-Regulation
apoptosis
Clinical Trials
cells
escape

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers. / Misale, Sandra; Bozic, Ivana; Tong, Jingshan; Peraza-Penton, Ashley; Lallo, Alice; Baldi, Federica; Lin, Kevin H.; Truini, Mauro; Trusolino, Livio; Bertotti, Andrea; Di Nicolantonio, Federica; Nowak, Martin A.; Zhang, Lin; Wood, Kris C.; Bardelli, Alberto.

In: Nature Communications, Vol. 6, 8305, 22.09.2015.

Research output: Contribution to journalArticle

Misale, S, Bozic, I, Tong, J, Peraza-Penton, A, Lallo, A, Baldi, F, Lin, KH, Truini, M, Trusolino, L, Bertotti, A, Di Nicolantonio, F, Nowak, MA, Zhang, L, Wood, KC & Bardelli, A 2015, 'Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers', Nature Communications, vol. 6, 8305. https://doi.org/10.1038/ncomms9305
Misale, Sandra ; Bozic, Ivana ; Tong, Jingshan ; Peraza-Penton, Ashley ; Lallo, Alice ; Baldi, Federica ; Lin, Kevin H. ; Truini, Mauro ; Trusolino, Livio ; Bertotti, Andrea ; Di Nicolantonio, Federica ; Nowak, Martin A. ; Zhang, Lin ; Wood, Kris C. ; Bardelli, Alberto. / Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers. In: Nature Communications. 2015 ; Vol. 6.
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