Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

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• 作者：Andrea Cavazzoni^a ; ¹ ; Mara A. Bonelli^a ; ¹ ; Claudia Fumarola^a ; ^{claudia.fumarola@unipr.it} ; Silvia La Monica^a ; Kinda Airoud^a ; Ramona Bertoni^a ; Roberta R. Alfieri^a ; Maricla Galetti^a ; ^b ; Stefano Tramonti^a ; Elena Galvani^a ; Adrian L. Harris^c ; Lesley-Ann Martin^d ; Daniele Andreis^e ; Alberto Bottini^e ; Daniele Generali^e ; ^f ; Pier Giorgio Petronini^a
• 关键词：Breast ; Letrozole ; Resistance ; AKT ; mTOR
• 刊名：Cancer Letters
• 出版年：2012
• 期刊代码：44_03043835
• 类别：med
• 出版时间：1 October, 2012
• 卷：323
• 期：1
• 页码：77-87
• 文件大小：1452 K

摘要

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ER伪 plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.