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 language | English |
|---|---|
| Article number | 8305 |
| Journal | Nature Communications |
| Volume | 6 |
| DOIs | |
| Publication status | Published - Sep 22 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers
AU - Misale, Sandra
AU - Bozic, Ivana
AU - Tong, Jingshan
AU - Peraza-Penton, Ashley
AU - Lallo, Alice
AU - Baldi, Federica
AU - Lin, Kevin H.
AU - Truini, Mauro
AU - Trusolino, Livio
AU - Bertotti, Andrea
AU - Di Nicolantonio, Federica
AU - Nowak, Martin A.
AU - Zhang, Lin
AU - Wood, Kris C.
AU - Bardelli, Alberto
PY - 2015/9/22
Y1 - 2015/9/22
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms9305
DO - 10.1038/ncomms9305
M3 - Article
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8305
ER -