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 ERĪ±-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.