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Ref Type

Journal Article

PMID

(21358673)

Authors

Weigelt B, Warne PH, Downward J

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	30	29	2011 Jul 21	3222-33	Oncogene

URL

Abstract Text

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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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PTEN	A72fs	frameshift	loss of function - predicted	PTEN A72fs results in a change in the amino acid sequence of the Pten protein beginning at aa 72 of 403, likely resulting in premature truncation of the functional protein (UniProt.org). A72fs results in lack of protein expression in culture (PMID: 21358673), and due to the effects of other truncation mutations downstream of A72 (PMID: 10468583), is predicted to lead to a loss of Pten protein function.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA act mut PTEN wild-type	breast cancer	sensitive	Torkinib	Preclinical - Cell culture	Actionable	In a preclinical study, 9/9 breast cancer cell lines harboring a PIK3CA activating mutation and PTEN wild-type demonstrated sensitivity to treatment with Torkinib (PP242) in culture, resulting in decreased cell viability (PMID: 21358673).	21358673
PIK3CA act mut PTEN wild-type	breast cancer	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, 8/9 breast cancer cell lines harboring a PIK3CA activating mutation and PTEN wild-type demonstrated sensitivity to treatment with Afinitor (everolimus) in culture, resulting in decreased cell viability (PMID: 21358673).	21358673
PIK3CA wild-type PTEN loss	breast cancer	sensitive	Selumetinib + Torkinib	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells harboring PIK3CA wild-type and PTEN loss demonstrated sensitivity to the combination treatment of Torkinib (PP242) and Selumetinib (AZD6244) in culture (PMID: 21358673).	21358673
PIK3CA wild-type PTEN loss	breast cancer	no benefit	Everolimus + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells harboring PIK3CA wild-type and PTEN loss did not demonstrate any benefit when treated with a combination of Afinitor (everolimus) and Selumetinib (AZD6244) (PMID: 21358673).	21358673
PIK3CA wild-type PTEN loss	breast cancer	no benefit	Everolimus + U0126	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells harboring PIK3CA wild-type and PTEN loss did not demonstrate any benefit when treated with a combination of Afinitor (everolimus) and U0126 (PMID: 21358673).	21358673
PIK3CA wild-type PTEN loss	breast cancer	sensitive	Torkinib + U0126	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells harboring PIK3CA wild-type and PTEN loss demonstrated sensitivity to the combination treatment of Torkinib (PP242) and U0126 in culture (PMID: 21358673).	21358673
PTEN loss	breast cancer	resistant	Torkinib	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cell lines with PTEN loss demonstrated resistance to Torkinib (PP242) in culture (PMID: 21358673).	21358673
PTEN loss	breast cancer	resistant	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, 10/12 breast cancer cell lines with PTEN loss demonstrated resistance to Afinitor (everolimus) in culture (PMID: 21358673).	21358673

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