The dual mTORC1/2 inhibitor, AZD2014, potentiates the efficacy of palbociclib, a CDK4/6 inhibitor, in ER+ breast cancer.


Year:

Session type:

Anna Staniszewska1,Chrysiis Michaloglou1,Claire Crafter1,Urszula Polanska1,Oona Delpuech1,Jon Curwen1,Mandy Lawson1,Larissa Carnevalli1,Michael Dymond1,Robert McEwen1,Sabina Cosulich1
1Astra Zeneca

Abstract

Background

Cyclin D1 with CDK4/6 are key regulators of the cell cycle progression from G1 to S phase. They form a complex which upon activation phosphorylates the retinoblastoma protein (Rb), leading to transcription of E2F target genes and entry into S phase. ER+ breast cancer cells often depend on cyclin D1 for the cell cycle progression, and are thus sensitive to CDK4/6 inhibitors, such as palbociclib. However, the anti-tumour effects of palbociclib are not durable, mainly due to early adaptation and resistance. It is of interest to investigate alternative agents that combined with palbociclib and endocrine therapy would result in enhanced efficacy.

We investigate whether the combination of vistusertib/AZD2014 (dual mTORC1/mTORC2 inhibitor) with palbociclib has  beneficial effects over either agent used as monotherapy in ER+ breast cancer.

Method

The combination effects of AZD2014 and palbociclib were investigated in the ER+ breast cancer cell line, MCF7. This includes growth and cell cycle analysis, gene and protein expression profiling, as well as tumour growth inhibition in mouse xenograft models.

Results

We demonstrate that combined mTORC1/2 and CDK4/6 inhibition has a strong anti-proliferative effect in the ER+ breast cancer cell line MCF7 in vitro and in vivo. This combination causes enhanced inhibition of the Rb-E2F pathway and increased induction of G1 cell cycle arrest. Although the lack of proliferation is sustained in the presence of the treatment, it is not maintained upon treatment withdrawal and regrowth is observed both in vitro and in vivo. Moreover, triple combination of AZD2014, palbociclib and endocrine therapy in vivo leads to tumour regression and this effect is sustained even following treatment withdrawal.

Conclusion

The data indicates that combined inhibition mTORC1/2 and CDK4/6 provides synergistic effect on growth inhibition of ER+ breast cancer by suppression of the Rb-E2F pathway. However, addition of endocrine therapy appears necessary to obtain a durable tumour regression.