AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo.

PI3K/AKT/mTOR signaling plays an important role in breast cancer. Its interaction with estrogen receptor (ER) signaling becomes more complex and interdependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility; however, a negative feedback loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve breast cancer treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER(+) breast cancer cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term estrogen deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 < 500 nmol/L) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50 ∼ 100 nmol/L). AZD5363 resensitized TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context-specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen response elements located on the TFF1, PGR, and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5, and IGFI signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER(+) patient-derived xenograft and delayed tumor progression after cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for breast cancer that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.

Ribas R ，Pancholi S ，Guest SK ，Marangoni E ，Gao Q ，Thuleau A ，Simigdala N ，Polanska UM ，Campbell H ，Rani A ，Liccardi G ，Johnston S ，Davies BR ，Dowsett M ，Martin LA ... -  《-》

Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation.

Fox EM ，Kuba MG ，Miller TW ，Davies BR ，Arteaga CL ... -  《-》

Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation.

Guest SK ，Ribas R ，Pancholi S ，Nikitorowicz-Buniak J ，Simigdala N ，Dowsett M ，Johnston SR ，Martin LA ... -  《PLoS One》

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro.

Jordan NJ ，Dutkowski CM ，Barrow D ，Mottram HJ ，Hutcheson IR ，Nicholson RI ，Guichard SM ，Gee JM ... -  《-》

Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.

Fu X ，Creighton CJ ，Biswal NC ，Kumar V ，Shea M ，Herrera S ，Contreras A ，Gutierrez C ，Wang T ，Nanda S ，Giuliano M ，Morrison G ，Nardone A ，Karlin KL ，Westbrook TF ，Heiser LM ，Anur P ，Spellman P ，Guichard SM ，Smith PD ，Davies BR ，Klinowska T ，Lee AV ，Mills GB ，Rimawi MF ，Hilsenbeck SG ，Gray JW ，Joshi A ，Osborne CK ，Schiff R ... -  《-》