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.
Highlights
Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer
A representative image is shown in (b), and quantification in (c). d LC50 of the IGF-1Rki was determined in these cells using the Alamar survival assay e) Correlation was assessed between the LC50 of IGF-1Rki and the HR functionality of cells
Recent work has suggested a role for BRCA1/2 and defective HR in sporadic ovarian cancer resulting from somatic mutations or epigenetic mechanisms
Summary
Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Amin et al BMC Cancer (2015) 15:817 women carrying BRCA1/2 germline mutations are at an increased risk of developing ovarian and breast cancer [5,6,7,8]. These mutations in BRCA1/2 genes exhibit impaired cellular ability to repair double-stranded DNA breaks via the homologous recombination (HR) repair pathway, leading to reduced RAD51 foci formation following DNA damage [9, 10]. In cancer cells with loss of function of proteins involved in HR including BRCA1/2, and RAD51, ATM or ATR, Poly (ADP-ribose) polymerase (PARP) inhibition, which interferes with single stranded DNA repair, has been shown to induce specific cancer cell killing, called synthetic lethality [11]
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