Reference Detail

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 Oncogene
Vol 30
Issue 29
Date 2011 Jul 21
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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
A72fs missense loss of function - predicted PTEN A72fs results in a change in the amino acid sequence of the Apc protein beginning at aa 72 of 403, likely resulting in premature truncation of the functional protein ( A72fs is predicted to confer a loss of function to the Pten protein, as demonstrated by the loss of all known functional domains ( and lack of protein expression in culture (PMID: 21358673).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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