Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells

Andreas Höglund; Lisa M Nilsson; Somsundar Veppil Muralidharan; Lisa A Hasvold; Philip Merta; Martina Rudelius; Viktoriya Nikolova; Ulrich Keller; Jonas A Nilsson

doi:10.1158/1078-0432.CCR-11-1198

Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells

Andreas Höglund, Lisa M Nilsson, Somsundar Veppil Muralidharan, Lisa A Hasvold, Philip Merta, Martina Rudelius, Viktoriya Nikolova, Ulrich Keller, Jonas A Nilsson

UWA Centre for Medical Research (affiliated with the Harry Perkins Institute of Medical Research)

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

118 Citations (Scopus)

Abstract

PURPOSE: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1).

EXPERIMENTAL DESIGN: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells.

RESULTS: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma.

CONCLUSION: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers.

Original language	English
Pages (from-to)	7067-79
Number of pages	13
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume	17
Issue number	22
DOIs	https://doi.org/10.1158/1078-0432.CCR-11-1198
Publication status	Published - 15 Nov 2011

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10.1158/1078-0432.CCR-11-1198

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Höglund, A., Nilsson, L. M., Muralidharan, S. V., Hasvold, L. A., Merta, P., Rudelius, M., Nikolova, V., Keller, U., & Nilsson, J. A. (2011). Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research, 17(22), 7067-79. https://doi.org/10.1158/1078-0432.CCR-11-1198

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abstract = "PURPOSE: The transcription factor c-Myc (or {"}Myc{"}) is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1).EXPERIMENTAL DESIGN: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells.RESULTS: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma.CONCLUSION: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers.",

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author = "Andreas H{\"o}glund and Nilsson, {Lisa M} and Muralidharan, {Somsundar Veppil} and Hasvold, {Lisa A} and Philip Merta and Martina Rudelius and Viktoriya Nikolova and Ulrich Keller and Nilsson, {Jonas A}",

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Höglund, A, Nilsson, LM, Muralidharan, SV, Hasvold, LA, Merta, P, Rudelius, M, Nikolova, V, Keller, U & Nilsson, JA 2011, 'Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 17, no. 22, pp. 7067-79. https://doi.org/10.1158/1078-0432.CCR-11-1198

Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells. / Höglund, Andreas; Nilsson, Lisa M; Muralidharan, Somsundar Veppil et al.
In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 17, No. 22, 15.11.2011, p. 7067-79.

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

TY - JOUR

T1 - Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells

AU - Höglund, Andreas

AU - Nilsson, Lisa M

AU - Muralidharan, Somsundar Veppil

AU - Hasvold, Lisa A

AU - Merta, Philip

AU - Rudelius, Martina

AU - Nikolova, Viktoriya

AU - Keller, Ulrich

AU - Nilsson, Jonas A

PY - 2011/11/15

Y1 - 2011/11/15

N2 - PURPOSE: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1).EXPERIMENTAL DESIGN: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells.RESULTS: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma.CONCLUSION: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers.

AB - PURPOSE: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1).EXPERIMENTAL DESIGN: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells.RESULTS: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma.CONCLUSION: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers.

KW - Animals

KW - Caspases/metabolism

KW - Cell Line, Tumor

KW - Checkpoint Kinase 1

KW - Humans

KW - Lymphoma, B-Cell/metabolism

KW - Mice

KW - Protein Kinase Inhibitors/pharmacology

KW - Protein Kinases/metabolism

KW - Proto-Oncogene Proteins c-myc/metabolism

U2 - 10.1158/1078-0432.CCR-11-1198

DO - 10.1158/1078-0432.CCR-11-1198

M3 - Article

C2 - 21933891

SN - 1078-0432

VL - 17

SP - 7067

EP - 7079

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

IS - 22

ER -

Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells

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