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PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

Oncogene volume 30, pages 3222–3233 (2011)Cite this article

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly activated in breast cancers due to frequent mutations in PIK3CA, loss of expression of PTEN or over-expression of receptor tyrosine kinases. PI3K pathway activation leads to stimulation of the key growth and proliferation regulatory kinase mammalian target of rapamycin (mTOR), which can be inhibited by rapamycin analogues and by kinase inhibitors; the effectiveness of these drugs in breast cancer treatment is currently being tested in clinical trials. To identify the molecular determinants of response to inhibitors that target mTOR via different mechanisms in breast cancer cells, we investigated the effects of pharmacological inhibition of mTOR using the allosteric mTORC1 inhibitor everolimus and the active-site mTORC1/mTORC2 kinase inhibitor PP242 on a panel of 31 breast cancer cell lines. We demonstrate here that breast cancer cells harbouring PIK3CA mutations are selectively sensitive to mTOR allosteric and kinase inhibitors. However, cells with PTEN loss of function are not sensitive to these drugs, suggesting that the functional consequences of these two mechanisms of activation of the mTOR pathway are quite distinct. In addition, a subset of HER2-amplified cell lines showed increased sensitivity to PP242, but not to everolimus, irrespective of the PIK3CA/PTEN status. These selective sensitivities were confirmed in more physiologically relevant three-dimensional cell culture models. Our findings provide a rationale to guide selection of breast cancer patients who may benefit from mTOR inhibitor therapy and highlight the importance of accurately assessing the expression of PTEN protein and not just its mutational status.

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Acknowledgements

We thank Miriam Molina Arcas, Ralph Fritsch, Elza de Bruin, Charles Swanton (CRUK London Research Institute) and Maryou Lambros and Jorge Reis-Filho (Breakthrough Breast Cancer Centre, London, UK) for helpful discussions, technical advice or critical reading of the manuscript, members of the LRI Equipment Park for sequencing and of the LRI FACS facility for cell-cycle analysis. We thank Morri Feldman and Kevan Shokat (UCSF) for providing PP242. This work was funded by Cancer Research UK.

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    B Weigelt, P H Warne & J Downward

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Weigelt, B., Warne, P. & Downward, J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 30, 3222–3233 (2011). https://doi.org/10.1038/onc.2011.42

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