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

doi:10.1038/ncomms9305

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

Istituto Oncologico Candiolo

Research output: Contribution to journal › Article › peer-review

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	https://doi.org/10.1038/ncomms9305
Publication status	Published - Sep 22 2015

ASJC Scopus subject areas

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

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10.1038/ncomms9305

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Misale, S., Bozic, I., Tong, J., Peraza-Penton, A., Lallo, A., Baldi, F., Lin, K. H., Truini, M., Trusolino, L., Bertotti, A., Di Nicolantonio, F., Nowak, M. A., Zhang, L., Wood, K. C., & Bardelli, A. (2015). Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers. Nature Communications, 6, [8305]. https://doi.org/10.1038/ncomms9305

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 › peer-review

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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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.",

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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

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

Abstract

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