Abstract PD4-03: CDK4/6 inhibition blocks effects of IGFs and insulin in estrogen receptor positive and triple negative breast cancers: Implications for cotargeting IGF1R/IR and CDKs

Abstract

Abstract IGF and insulin signaling via the type I insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) respectively, are potent activators of PI3K/Akt/mTOR. Drugs targeting IGF1R and the related IR were tested clinically including in combination with mTOR inhibitors. Inhibition of mTOR was not effective as inhibition of mTOR relieved the negative feedback loop regulating levels of the adaptor protein, insulin receptor substrate 1 (IRS-1), that mediates proliferative effects of IGFs and insulin and rapamycin enhanced phosphorylation of Akt. The ribosomal protein S6 kinase (S6K) phosphorylates IRS-1 on serine residues and targets it for proteasomal degradation and this negative feedback regulation is important in attenuating IGF and insulin signaling. Cyclin dependent kinases (CDKs) 4 and 6 are required for cell cycle progression. CDK4/6 inhibitors have recently been approved for treatment of estrogen receptor positive (ER+), Her2- advanced breast cancers and these CDK4/6 inhibitors such as palbociclib block phosphorylation of retinoblastoma (Rb). IGFs and insulin stimulate cell cycle progression and increase cyclin D1 levels in breast cancers. Therefore, we hypothesized that CDK4/6 inhibition can be combined with IGF1R/IR targeting to block mitogenic functions of IGF/insulin signaling in breast cancer as this would not relieve the negative feedback regulation of IGF and insulin signaling. Herein, we analyzed the effect of palbociclib on IGF-I/insulin signaling, Rb phosphorylation and growth of various subtypes of breast cancer cells. Palbociclib blocked growth of both endocrine sensitive and resistant ER+ breast cancers. Further, ER+ parental MCF-7 and T47D cells that respond to hormonal therapy including tamoxifen, a selective estrogen receptor modulator, were more sensitive to palbociclib compared to matched cells with acquired resistance to tamoxifen. Palbociclib blocked IGF-I and insulin stimulated entry into cell cycle leading to G0/G1 arrest in ER+ breast cancer cells. Further, palbociclib also blocked growth and cell cycle progression of triple negative breast cancer (TNBC) cells. Unlike mTOR inhibitors that upregulated IRS-1 levels leading to increased phosphorylation of Akt through IGF1R/IR, palbociclib did not affect IRS-1 levels and did not enhance phosphorylation of Akt in ER+ and TNBC cells. Further, combination of palbociclib with IGF1R inhibitory antibody was more effective in inhiibiting growth of ER+ breast cancer cells. Our data show that palbociclib can be a potential therapeutic strategy for TNBC and that combining IGF1R/IR inhibitors with palbociclib may be superior to combining them with mTOR inhibitors for ER+ breast cancer. Citation Format: Sachdev D, Hoff K. CDK4/6 inhibition blocks effects of IGFs and insulin in estrogen receptor positive and triple negative breast cancers: Implications for cotargeting IGF1R/IR and CDKs [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-03.