Molecular characterization of anastrozole resistance in breast cancer: Pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK‐2206 with an aromatase inhibitor

Abstract

Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ERa)-positive breast cancers. The Res-Ana cells, a new model of acquired resistance to anastrozole, were established by longterm exposure of aromatase-overexpressing MCF-7 cells to this drug. These resistant cells developed ER-independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ERa antagonists. They also displayed a constitutive activation of the PI3K=Akt=mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho-Akt=Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce de novo resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK-2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole-acquired resistance based on the selection of cancer-initiating-like cells possessing self-renewing properties, intrinsic resistance to anastrozole and sensitivity to MK-2206. Altogether, our work demonstrated that the Akt=mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt=mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone-dependent breast cancer patients.In 60% of premenopausal patients and 75% of postmenopausal patients, breast cancer is a hormone-dependent disease that relies on the mitogenic effects of estrogen to drive carcinogenesis. Aromatase inhibitors (AIs) are now considered to be the standard of care for postmenopausal patients with estrogen receptor alpha (ERa)-positive (ER1) breast cancer as they have proven to be more effective than the selective estrogen receptor modulator tamoxifen (Tam). 1 Despite the proven clinical efficacy of AIs, de novo and acquired resistance still occurs and constitutes a major impediment to successful therapy.The mechanisms involved in resistance to AIs remain poorly described and few cellular models mimicking resistance to AIs are currently available. Aromatase-transfected and longterm estrogen-deprived (LTED) cell lines have been proposed as cellular models of resistance to AIs, based on the hypothesis that lack of hormone in the environment could mimic the withdrawal of estrogen that occurs during treatment with AIs. 2,3 However, several studies suggest that the molecular events taking place during estrogen deprivation may differ from those occurring during AI exposure. 2-4 Thus, cellular Key words: breast cancer, endocrine therapy, anastrozole resistance, Akt=mTOR pathway, sig...

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

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