Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors

Abstract

BackgroundImpairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Tumors with BRCA1 mutations show increased expression of the Insulin-like growth factor type 1 receptor (IGF-1R). We previously have shown that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian tumor cells. In the current study, we aimed to investigate the correlation between HR and sensitivity to IGF-1R inhibition. Further, we hypothesized that IGF-1R inhibition might sensitize HR proficient cancers to Poly ADP ribose polymerase (PARP) inhibitors.MethodsUsing ovarian and breast cancer cellular models with known BRCA1 status, we evaluated their HR functionality by RAD51 foci formation assay. The 50 % lethal concentration (LC50) of Insulin-like growth factor type 1 receptor kinase inhibitor (IGF-1Rki) in these cells was assessed, and western immunoblotting was performed to determine the expression of proteins involved in the IGF-1R pathway. Moreover, IGF-1R inhibitors were added on HR proficient cell lines to assess mRNA and protein expression of RAD51 by qPCR and western blot. Also, we explored the interaction between RAD51 and Insulin receptor substance 1 (IRS-1) by immunoprecipitation. Next, combination effect of IGF-1R and PARP inhibitors was evaluated by clonogenic assay.ResultsCells with mutated/methylated BRCA1 showed an impaired HR function, and had an overactivation of the IGF-1R pathway. These cells were more sensitive to IGF-1R inhibition compared to HR proficient cells. In addition, the IGF-IR inhibitor reduced RAD51 expression at mRNA and protein levels in HR proficient cells, and sensitized these cells to PARP inhibitor.ConclusionTargeting IGF-1R might lead to improved personalized therapeutic approaches in cancer patients with HR deficiency. Targeting both PARP and IGF-1R might increase the clinical efficacy in HR deficient patients and increase the population of patients who may benefit from PARP inhibitors.

The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…Therefore, nuclear hormone receptor activation is PARP-dependent. Insulin-like growth factor (IGF)-1 signaling is potentiated by PARP inhibition (Amin et al 2015). Furthermore, PARP1 interferes with GLP-1 signaling that may interfere with insulin secretion from β cells (Liu et al 2011).…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…Most important to the development of more effective IGF1R-targeted therapies, PARP regulation in the ER-positive MCF7 and HER2-positive BT474 cell lines is mediated via IGF1R (Kim et al 2015). Preclinical support for the use of dual IGF1R and PARP inhibitors is highlighted by a study that showed an increased sensitivity to olaparib by the addition of the IGF1R inhibitor, BMS-536924, in BRCA1-mutated (MDA-MB-436 and HCC1937) compared with BRCA1 wild-type (BT20 and MDA-MB-231) TNBC cell lines (Table 2) (Amin et al 2015). There is also compelling evidence that IGFBP-3 is involved in DNA damage repair, highlighting the need for further investigation of the role of IGF-1-signaling in the DNA repair process in breast cancer .…”

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors

“…Therefore, following DNA damage through single-strand breaks, inhibition of PARP-1 leads to accumulation of DSB’s in HR-deficient cells, such as BRCA1/2-mutated cells. This effect is toxic and induces apoptosis [ 16 – 20 ]. This mechanism of targeted therapy has been named synthetic lethality.…”