Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

Jatin Roper; Mark J. Sinnamon; Erin M. Coffee; Peter Belmont; Lily Keung; Larissa Georgeon-Richard; Wei Vivian Wang; Anthony C. Faber; Jihye Yun; Ömer H. Yilmaz; Roderick T. Bronson; Eric S. Martin; Philip N. Tsichlis; Kenneth E. Hung

doi:10.1016/j.canlet.2014.02.018

Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

Jatin Roper, Mark J. Sinnamon, Erin M. Coffee, Peter Belmont, Lily Keung, Larissa Georgeon-Richard, Wei Vivian Wang, Anthony C. Faber, Jihye Yun, Ömer H. Yilmaz, Roderick T. Bronson, Eric S. Martin, Philip N. Tsichlis, Kenneth E. Hung

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

35 Scopus citations

Abstract

PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.

Original language	English (US)
Pages (from-to)	204-211
Number of pages	8
Journal	Cancer Letters
Volume	347
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2014.02.018
State	Published - Jun 1 2014
Externally published	Yes

Keywords

Colorectal cancer
KRAS
MEK
Mouse model of cancer
PI3K

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2014.02.018

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Roper, J., Sinnamon, M. J., Coffee, E. M., Belmont, P., Keung, L., Georgeon-Richard, L., Wang, W. V., Faber, A. C., Yun, J., Yilmaz, Ö. H., Bronson, R. T., Martin, E. S., Tsichlis, P. N., & Hung, K. E. (2014). Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Letters, 347(2), 204-211. https://doi.org/10.1016/j.canlet.2014.02.018

Roper, J, Sinnamon, MJ, Coffee, EM, Belmont, P, Keung, L, Georgeon-Richard, L, Wang, WV, Faber, AC, Yun, J, Yilmaz, ÖH, Bronson, RT, Martin, ES, Tsichlis, PN & Hung, KE 2014, 'Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer', Cancer Letters, vol. 347, no. 2, pp. 204-211. https://doi.org/10.1016/j.canlet.2014.02.018

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title = "Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer",

abstract = "PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.",

keywords = "Colorectal cancer, KRAS, MEK, Mouse model of cancer, PI3K",

author = "Jatin Roper and Sinnamon, {Mark J.} and Coffee, {Erin M.} and Peter Belmont and Lily Keung and Larissa Georgeon-Richard and Wang, {Wei Vivian} and Faber, {Anthony C.} and Jihye Yun and Yilmaz, {{\"O}mer H.} and Bronson, {Roderick T.} and Martin, {Eric S.} and Tsichlis, {Philip N.} and Hung, {Kenneth E.}",

year = "2014",

month = jun,

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doi = "10.1016/j.canlet.2014.02.018",

language = "English (US)",

volume = "347",

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AU - Roper, Jatin

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AU - Coffee, Erin M.

AU - Belmont, Peter

AU - Keung, Lily

AU - Georgeon-Richard, Larissa

AU - Wang, Wei Vivian

AU - Faber, Anthony C.

AU - Yun, Jihye

AU - Yilmaz, Ömer H.

AU - Bronson, Roderick T.

AU - Martin, Eric S.

AU - Tsichlis, Philip N.

AU - Hung, Kenneth E.

PY - 2014/6/1

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N2 - PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.

AB - PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.

KW - Colorectal cancer

KW - KRAS

KW - MEK

KW - Mouse model of cancer

KW - PI3K

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Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

Abstract

Keywords

ASJC Scopus subject areas

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