Abstract
BackgroundMammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option.MethodsUsing hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; “MK-0646”; anti-IGF-1R antibody), ridaforolimus (RIDA; “MK-8669”; mTORC1 small molecule inhibitor) and letrozole (“LET”, aromatase inhibitor).ResultsWith the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach.ConclusionThese data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2847-3) contains supplementary material, which is available to authorized users.
Highlights
Mammalian target of rapamycin represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases
Di Cosimo and colleagues recently reported that the combination of dalotuzumab (DALO; “MK-0646”; anti-insulin-like growth factor (IGF)-1R antibody) and ridaforolimus (RIDA; “MK-8669”; Mammalian target of rapamycin (mTOR) inhibitor) had evidence of antitumor activity in estrogen receptor positive (ER+)/proliferative breast cancer patients that were refractory to multiple chemotherapy regimens
IGF-1 receptor (IGF-1R) inhibition (MK-0646) does not enhance hormonal therapy in MCF-7/AC-1 xenografts Based on our previous investigations demonstrating enhanced activity of hormonal therapy in combination with IGF inhibition, the in vivo anti-tumor potential of MK-0646 plus letrozole (LET) or tamoxifen (TAM) was determined [10] (Fig. 1)
Summary
Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. Secondary resistance to mTOR inhibitors remains problematic as suppression of negative feedback inhibition via mTORC1 blockade can induce the IGF type-1 receptor (IGF-1R) and subsequently increase both PI3K and MAPK signaling cascades [2, 3]. Additional findings from this study suggest that more aggressive ER-positive luminal B subtype tumors exhibited high IGF signaling activation and low RAS pathway activation and that combined MK-8669/MK-0646 combination therapy may be most appropriate for this subset of patients. These data suggest that combination MK-0646 and MK-8669 may be a promising new regimen for ER-positive breast cancer patients whom may have limited benefit from hormonal therapy [4]
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