Dual inhibition of PI3K and mTOR mitigates feedback-loop pAkt activation to improve tamoxifen response in breast cancer cells
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'ajouter un inhibiteur de PI3K à l'everolimus, un inhibiteur de mTOR, pour le traitement d'un cancer du sein ER+
Everolimus, a mTOR inhibitor, showed great antitumor efficacy with tamoxifen, letrozole or exemestane in clinical treatment of estrogen receptor (ER) positive breast cancer. However, its anti-tumor activity was compromised by pAkt activation through the feedback-loop pathway. Here, we evaluated whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In MCF-7 and BT474 breast cancer cell lines, we observed that everolimus inhibited the mTOR downstream activity by decreasing p-p70S6k and p-4EBP1 expression, which also resulted in pAkt473 activation. However, adding a PI3K inhibitor, LY294002, to tamoxifen and everolimus treatment gained better antitumor effect compared with tamoxifen or other two agents' combination. Meanwhile, we found that LY294002 was capable of suppressing PI3K/Akt/mTOR pathway activity and mitigating pAkt473 feedback-loop activation in both cell lines. Moreover, this combining scheme also significantly inhibited HIF-1α expression in a hypoxic condition, an angiogenesis marker, followed by reducing blood vessel sprout formation in vitro assays. Finally, we demonstrated that three agents combination treatment in MCF-7 xenografts model had the greatest efficacy in inhibiting tumor growth and angiogenesis. Taken together, our results suggest that dual inhibition of PI3K and mTOR may further improve endocrine therapy efficacy in the treatment of ER positive breast cancer.