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Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells
Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Em...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392104/ https://www.ncbi.nlm.nih.gov/pubmed/22668349 http://dx.doi.org/10.1042/BSR20120050 |
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author | Yuen, Hiu-Fung Abramczyk, Olga Montgomery, Grant Chan, Ka-Kui Huang, Yu-Han Sasazuki, Takehiko Shirasawa, Senji Gopesh, Srivastava Chan, Kwok-Wah Fennell, Dean Janne, Pasi El-Tanani, Mohamed Murray, James T. |
author_facet | Yuen, Hiu-Fung Abramczyk, Olga Montgomery, Grant Chan, Ka-Kui Huang, Yu-Han Sasazuki, Takehiko Shirasawa, Senji Gopesh, Srivastava Chan, Kwok-Wah Fennell, Dean Janne, Pasi El-Tanani, Mohamed Murray, James T. |
author_sort | Yuen, Hiu-Fung |
collection | PubMed |
description | Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy. |
format | Online Article Text |
id | pubmed-3392104 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-33921042012-07-12 Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells Yuen, Hiu-Fung Abramczyk, Olga Montgomery, Grant Chan, Ka-Kui Huang, Yu-Han Sasazuki, Takehiko Shirasawa, Senji Gopesh, Srivastava Chan, Kwok-Wah Fennell, Dean Janne, Pasi El-Tanani, Mohamed Murray, James T. Biosci Rep Original Paper Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy. Portland Press Ltd. 2012-07-04 2012-08-01 /pmc/articles/PMC3392104/ /pubmed/22668349 http://dx.doi.org/10.1042/BSR20120050 Text en © 2012 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited |
spellingShingle | Original Paper Yuen, Hiu-Fung Abramczyk, Olga Montgomery, Grant Chan, Ka-Kui Huang, Yu-Han Sasazuki, Takehiko Shirasawa, Senji Gopesh, Srivastava Chan, Kwok-Wah Fennell, Dean Janne, Pasi El-Tanani, Mohamed Murray, James T. Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title_full | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title_fullStr | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title_full_unstemmed | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title_short | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
title_sort | impact of oncogenic driver mutations on feedback between the pi3k and mek pathways in cancer cells |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392104/ https://www.ncbi.nlm.nih.gov/pubmed/22668349 http://dx.doi.org/10.1042/BSR20120050 |
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