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

Publication ,  Journal Article
Misale, S; Bozic, I; Tong, J; Peraza-Penton, A; Lallo, A; Baldi, F; Lin, KH; Truini, M; Trusolino, L; Bertotti, A; Di Nicolantonio, F ...
Published in: Nat Commun
September 22, 2015

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.

Duke Scholars

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 22, 2015

Volume

6

Start / End Page

8305

Location

England

Related Subject Headings

  • Transplantation, Heterologous
  • Panitumumab
  • Neoplasms, Experimental
  • Mitogen-Activated Protein Kinase Kinases
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • ErbB Receptors
  • Drug Resistance, Neoplasm
  • Colorectal Neoplasms
 

Citation

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MLA
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Misale, S., Bozic, I., Tong, J., Peraza-Penton, A., Lallo, A., Baldi, F., … Bardelli, A. (2015). Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers. Nat Commun, 6, 8305. https://doi.org/10.1038/ncomms9305

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 22, 2015

Volume

6

Start / End Page

8305

Location

England

Related Subject Headings

  • Transplantation, Heterologous
  • Panitumumab
  • Neoplasms, Experimental
  • Mitogen-Activated Protein Kinase Kinases
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • ErbB Receptors
  • Drug Resistance, Neoplasm
  • Colorectal Neoplasms