Abstract 2303: CDK4/6 inhibition blocks effects of IGFs and insulin in estrogen receptor positive and triple negative breast cancers

Abstract

Abstract Insulin-like growth factors (IGFs) and insulin signaling via the type I IGF 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. Palbociclib blocked growth of ER+ parental MCF-7 and T47D breast cancer cells that respond to hormonal therapy including tamoxifen, a selective estrogen receptor modulator. Parental MCF-7 and T47D were more sensitive to palbociclib compared to matched cells with acquired resistance to tamoxifen (MCF-7/TamR and T47D/TamR). Palbociclib also blocked IGF-I and insulin stimulated entry into cell cycle leading to G0/G1 arrest in ER+ breast cancer cells. Combination of palbociclib with an IGF1R inhibitory antibody, but not IR antibody, was more effective in inhibiting growth of tamoxifen sensitive parental ER+ breast cancer cells. In contrast combination of palbociclib with an IR antibody was effective in inhibition of MCF-7/TamR 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, palbociclib also blocked growth and cell cycle progression of triple negative breast cancer (TNBC) cells. Our data show that combining IGF1R/IR inhibitors with palbociclib may be superior to combining them with mTOR inhibitors for ER+ breast cancer and palbociclib can be a potential therapeutic strategy for TNBC. These data implicate that cotargeting CDK4/6 and IR could be a therapeutic option for patients with endocrine resistant disease. Citation Format: Katelyn Hoff, Deepali Sachdev. CDK4/6 inhibition blocks effects of IGFs and insulin in estrogen receptor positive and triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2303.