Initial preclinical VE-822? studies demon strated that tamoxifen resistance is mediated in part by mTOR signalling. This contributed towards the rationale for successful clinical studies where rapalogue treatment was combined with aromatase inhibitor or tamoxifen therapy which resulted in approval of the rapalogue everolimus, in combination Inhibitors,Modulators,Libraries with the steroidal aro matase inhibitor exemestane, for treatment of post menopausal women with advanced ER HER2 breast cancer progressing on a non steroidal aromatase inhibitor. Critically, however, although the BOLERO 2 trial showed that the objective response rate was im proved for everolimus antihormone combination versus antihormone alone, no patients showed complete re sponse and some patients remained refractory to this rapalogue therapy or developed resistance during treat ment.
The signalling pathways that limit the impact of rapalogues in endocrine resistant breast cancer have to date been largely undefined. Here, we have studied the use of the mTOR kinase inhibitor AZD8055 as a potential treatment for acquired endocrine resistant breast cancers including those refractory to rapalogue treatment. Inhibitors,Modulators,Libraries Importance of mTORC2 AKT signalling in acquired endocrine resistant models resistant Inhibitors,Modulators,Libraries to rapalogue RAD001 Our study has predominantly focussed on MCF7 X and TamR cells as in vitro models that aim to represent clinical relapse after first line oestrogen deprivation or tamoxifen treatment, respectively. Interestingly, we found that MCF7 X cell growth was completely, and TamR cells partially, resistant to inhibition by RAD001, despite inhibition of target TORC1 signalling.
Similar growth and signalling effects have been reported by others in MCF 7 cells with acquired tamoxifen resistance. Critically, in our study RAD001 failed Inhibitors,Modulators,Libraries to inhibit the mTORC2 signalling complex which is a major regulator Inhibitors,Modulators,Libraries of Akt activity. Thus, p mTORser2481, p Aktser473 and also growth, growth in TamR and MCF7 X cells. To the best of our knowledge, this is the first report suggesting the potential for mTOR kinase inhibitors in rapalogue insensitive ER HER2 breast can cer cells with acquired endocrine resistance. Clearly, it should be remembered that there are limitations to studies based on homogeneous cell cultures because customer review such model ling cannot reflect the breadth of clinical heterogeneity of ER disease or microenvironment impact. How ever, experimental work has shown that resistant cell lines can reflect features seen in some clinical breast cancer which is in part AKT driven in TamR and MCF7 X cells, were not inhibited by this agent.