The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models

S V Holt; A Logié; R Odedra; A Heier; S P Heaton; D Alferez; B R Davies; R W Wilkinson; P D Smith

doi:10.1038/bjc.2012.8

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models

S V Holt, A Logié, R Odedra, A Heier, S P Heaton, D Alferez, B R Davies, R W Wilkinson, P D Smith

AstraZeneca

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

Abstract

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy.

METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations.

RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib.

CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

Original language	English
Pages (from-to)	858-66
Number of pages	9
Journal	British Journal of Cancer
Volume	106
Issue number	5
DOIs	https://doi.org/10.1038/bjc.2012.8
Publication status	Published - 28 Feb 2012

Keywords

Animals
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Benzimidazoles
Cell Line, Tumor
Cell Proliferation
Dacarbazine
Female
Humans
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP Kinase Signaling System
Mice
Mice, Nude
Mitogen-Activated Protein Kinase Kinases
Neoplasms, Experimental
Organophosphates
Protein Kinase Inhibitors
Quinazolines
Taxoids
Xenograft Model Antitumor Assays
Journal Article
Research Support, Non-U.S. Gov't

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/bjc.2012.8

Cite this

Holt, S. V., Logié, A., Odedra, R., Heier, A., Heaton, S. P., Alferez, D., Davies, B. R., Wilkinson, R. W., & Smith, P. D. (2012). The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. British Journal of Cancer, 106(5), 858-66. https://doi.org/10.1038/bjc.2012.8

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title = "The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models",

abstract = "BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy.METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations.RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib.CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.",

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author = "Holt, {S V} and A Logi{\'e} and R Odedra and A Heier and Heaton, {S P} and D Alferez and Davies, {B R} and Wilkinson, {R W} and Smith, {P D}",

year = "2012",

month = feb,

day = "28",

doi = "10.1038/bjc.2012.8",

language = "English",

volume = "106",

pages = "858--66",

journal = "British Journal of Cancer",

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Holt, SV, Logié, A, Odedra, R, Heier, A, Heaton, SP, Alferez, D, Davies, BR, Wilkinson, RW & Smith, PD 2012, 'The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models', British Journal of Cancer, vol. 106, no. 5, pp. 858-66. https://doi.org/10.1038/bjc.2012.8

TY - JOUR

T1 - The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models

AU - Holt, S V

AU - Logié, A

AU - Odedra, R

AU - Heier, A

AU - Heaton, S P

AU - Alferez, D

AU - Davies, B R

AU - Wilkinson, R W

AU - Smith, P D

PY - 2012/2/28

Y1 - 2012/2/28

N2 - BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy.METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations.RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib.CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

AB - BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy.METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations.RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib.CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

KW - Animals

KW - Antineoplastic Agents

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Apoptosis

KW - Benzimidazoles

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Dacarbazine

KW - Female

KW - Humans

KW - MAP Kinase Kinase 1

KW - MAP Kinase Kinase 2

KW - MAP Kinase Signaling System

KW - Mice

KW - Mice, Nude

KW - Mitogen-Activated Protein Kinase Kinases

KW - Neoplasms, Experimental

KW - Organophosphates

KW - Protein Kinase Inhibitors

KW - Quinazolines

KW - Taxoids

KW - Xenograft Model Antitumor Assays

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/bjc.2012.8

DO - 10.1038/bjc.2012.8

M3 - Article

C2 - 22343622

SN - 0007-0920

VL - 106

SP - 858

EP - 866

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 5

ER -

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

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