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

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 - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Concomitant blockade of EGFR and MEK halts the emergence of resistance in CRC cell lines.CCK81 (a), DiFi (b), C99 (c), NCIH508 (d) and HCA-46 (e). Cell lines were seeded at 20 million (CCK81 and C99) and 10 million (DiFi, NCIH508 and HCA-46) cell density and treated with cetuximab alone (340 nM), pimasertib alone (250 nM) and with the combination of the two drugs from day 0 or at the time of acquired resistance to cetuximab. Cells were detached and counted at least once a week as described in Methods section. A single biological replicate is represented for each cell model. Non-linear fit with exponential growth curve (Graphpad Prism) was applied to data points to show growth kinetics.
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f2: Concomitant blockade of EGFR and MEK halts the emergence of resistance in CRC cell lines.CCK81 (a), DiFi (b), C99 (c), NCIH508 (d) and HCA-46 (e). Cell lines were seeded at 20 million (CCK81 and C99) and 10 million (DiFi, NCIH508 and HCA-46) cell density and treated with cetuximab alone (340 nM), pimasertib alone (250 nM) and with the combination of the two drugs from day 0 or at the time of acquired resistance to cetuximab. Cells were detached and counted at least once a week as described in Methods section. A single biological replicate is represented for each cell model. Non-linear fit with exponential growth curve (Graphpad Prism) was applied to data points to show growth kinetics.

Mentions: In DiFi and CCK81, the TTP assay shows that inhibition of MEK alone had modest or no impact. We further found that resistance to cetuximab occurs within 80–120 days after therapy initiation depending on the cell line. Similar results were obtained in multiple CRC cell models (Fig. 2).


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

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 - Nat Commun (2015)

Concomitant blockade of EGFR and MEK halts the emergence of resistance in CRC cell lines.CCK81 (a), DiFi (b), C99 (c), NCIH508 (d) and HCA-46 (e). Cell lines were seeded at 20 million (CCK81 and C99) and 10 million (DiFi, NCIH508 and HCA-46) cell density and treated with cetuximab alone (340 nM), pimasertib alone (250 nM) and with the combination of the two drugs from day 0 or at the time of acquired resistance to cetuximab. Cells were detached and counted at least once a week as described in Methods section. A single biological replicate is represented for each cell model. Non-linear fit with exponential growth curve (Graphpad Prism) was applied to data points to show growth kinetics.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595628&req=5

f2: Concomitant blockade of EGFR and MEK halts the emergence of resistance in CRC cell lines.CCK81 (a), DiFi (b), C99 (c), NCIH508 (d) and HCA-46 (e). Cell lines were seeded at 20 million (CCK81 and C99) and 10 million (DiFi, NCIH508 and HCA-46) cell density and treated with cetuximab alone (340 nM), pimasertib alone (250 nM) and with the combination of the two drugs from day 0 or at the time of acquired resistance to cetuximab. Cells were detached and counted at least once a week as described in Methods section. A single biological replicate is represented for each cell model. Non-linear fit with exponential growth curve (Graphpad Prism) was applied to data points to show growth kinetics.
Mentions: In DiFi and CCK81, the TTP assay shows that inhibition of MEK alone had modest or no impact. We further found that resistance to cetuximab occurs within 80–120 days after therapy initiation depending on the cell line. Similar results were obtained in multiple CRC cell models (Fig. 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.

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.

No MeSH data available.


Related in: MedlinePlus