Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)

Sarah V Holt; Armelle Logie; Barry R Davies; Denis Alferez; Sarah Runswick; Sarah Fenton; Christine M Chresta; Yi Gu; Jingchuan Zhang; Yi-Long Wu; Robert W Wilkinson; Sylvie M Guichard; Paul D Smith

doi:10.1158/0008-5472.CAN-11-1780

Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)

Sarah V Holt, Armelle Logie, Barry R Davies, Denis Alferez, Sarah Runswick, Sarah Fenton, Christine M Chresta, Yi Gu, Jingchuan Zhang, Yi-Long Wu, Robert W Wilkinson, Sylvie M Guichard, Paul D Smith

AstraZeneca

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

Abstract

The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.

Original language	English
Pages (from-to)	1804-13
Number of pages	10
Journal	Cancer Research
Volume	72
Issue number	7
DOIs	https://doi.org/10.1158/0008-5472.CAN-11-1780
Publication status	Published - 1 Apr 2012

Keywords

Animals
Apoptosis
Benzimidazoles
Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Female
Gene Expression Profiling
Humans
Lung Neoplasms
MAP Kinase Signaling System
Mice
Mitogen-Activated Protein Kinase Kinases
Morpholines
Mutation
Neoplasms, Experimental
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Signal Transduction
TOR Serine-Threonine Kinases
Xenograft Model Antitumor Assays
ras Proteins
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)

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10.1158/0008-5472.CAN-11-1780

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Holt, S. V., Logie, A., Davies, B. R., Alferez, D., Runswick, S., Fenton, S., Chresta, C. M., Gu, Y., Zhang, J., Wu, Y.-L., Wilkinson, R. W., Guichard, S. M., & Smith, P. D. (2012). Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Research, 72(7), 1804-13. https://doi.org/10.1158/0008-5472.CAN-11-1780

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title = "Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)",

abstract = "The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.",

keywords = "Animals, Apoptosis, Benzimidazoles, Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Female, Gene Expression Profiling, Humans, Lung Neoplasms, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Morpholines, Mutation, Neoplasms, Experimental, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays, ras Proteins, Journal Article, Research Support, Non-U.S. Gov't",

author = "Holt, {Sarah V} and Armelle Logie and Davies, {Barry R} and Denis Alferez and Sarah Runswick and Sarah Fenton and Chresta, {Christine M} and Yi Gu and Jingchuan Zhang and Yi-Long Wu and Wilkinson, {Robert W} and Guichard, {Sylvie M} and Smith, {Paul D}",

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doi = "10.1158/0008-5472.CAN-11-1780",

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Holt, SV, Logie, A, Davies, BR, Alferez, D, Runswick, S, Fenton, S, Chresta, CM, Gu, Y, Zhang, J, Wu, Y-L, Wilkinson, RW, Guichard, SM & Smith, PD 2012, 'Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)', Cancer Research, vol. 72, no. 7, pp. 1804-13. https://doi.org/10.1158/0008-5472.CAN-11-1780

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T1 - Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)

AU - Holt, Sarah V

AU - Logie, Armelle

AU - Davies, Barry R

AU - Alferez, Denis

AU - Runswick, Sarah

AU - Fenton, Sarah

AU - Chresta, Christine M

AU - Gu, Yi

AU - Zhang, Jingchuan

AU - Wu, Yi-Long

AU - Wilkinson, Robert W

AU - Guichard, Sylvie M

AU - Smith, Paul D

PY - 2012/4/1

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N2 - The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.

AB - The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.

KW - Animals

KW - Apoptosis

KW - Benzimidazoles

KW - Carcinoma, Non-Small-Cell Lung

KW - Colorectal Neoplasms

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Lung Neoplasms

KW - MAP Kinase Signaling System

KW - Mice

KW - Mitogen-Activated Protein Kinase Kinases

KW - Morpholines

KW - Mutation

KW - Neoplasms, Experimental

KW - Protein Kinase Inhibitors

KW - Proto-Oncogene Proteins

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases

KW - Xenograft Model Antitumor Assays

KW - ras Proteins

KW - Journal Article

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

U2 - 10.1158/0008-5472.CAN-11-1780

DO - 10.1158/0008-5472.CAN-11-1780

M3 - Article

C2 - 22271687

SN - 0008-5472

VL - 72

SP - 1804

EP - 1813

JO - Cancer Research

JF - Cancer Research

IS - 7

ER -

Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055)

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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