Estrogen receptor positive (ER+) breast cancers are treated with hormonal therapies such as tamoxifen or aromatase inhibitors. More than 30% of patients with early-stage ER+ breast cancer treated with endocrine therapy will relapse and all patients with metastatic breast cancer expressing ER eventually acquire resistance to hormonal therapy. Endocrine therapy resistant patients therefore require novel therapeutic options. Insulin-like growth factors (IGFs) and insulin signaling via the type I IGF receptor (IGF1R) and insulin receptor (IR) respectively regulate breast cancer biology. Unfortunately, IGF1R targeted therapies failed to show a benefit in prolonging either disease-free or overall survival in clinical trials. In pre-clinical models acquired resistance to tamoxifen results in loss of IGF1R and enhanced sensitivity to IR signaling. Inhibition of mTOR alone relieves the negative feedback loop regulating levels of the adaptor protein IRS-1, which mediates proliferative effects of IGFs and insulin and enhanced phosphorylation of Akt. The ribosomal protein S6 kinase (S6K) phosphorylates IRS-1 on serine residues targeting 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 ER+, Her2- advanced breast cancers and these such as palbociclib and abemaciclib block phosphorylation of retinoblastoma. IGFs and insulin stimulate cell cycle progression and increase cyclin D1 levels in breast cancers. Therefore, we hypothesized that CDK4/6 inhibition combined with IGF1R or IR targeting, to block mitogenic functions of IGF or insulin signaling, could be a viable therapeutic option in endocrine sensitive and endocrine resistant breast cancer, respectively. 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. 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+ breast cancer cells. Combination of palbociclib with an IGF1R inhibitory antibody (huEM164), but not IR antibody (83-7), was better at inhibiting growth of endocrine sensitive MCF-7 and T-47D cells than either drug alone. Further, in a formal synergy study using the method of Chou-Talalay, the combination index of palbociclib and the IGF1R antibody was <1 for MCF-7 parent cells, indicating the two drugs synergistically inhibit growth. Combination of palbociclib with an IR antibody synergistically inhibited the growth of endocrine resistant MCF-7/TamR cells. Our data show that cotrageting CDK4/6 and IGF1R is more effective in endocrine sensitive but cotargeting CDK4/6 and IR is more effective in tamoxifen resistant breast cancer cells. These data indicate that targeting CDK4/6 and IR could be a therapeutic option for patients with endocrine resistant disease.

Citation Format: Hoff K, Sachdev D. Targeting CDK4/6 and IGF1R or insulin receptor synergistically inhibits growth of endocrine sensitive and endocrine resistant breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-20.

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.