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


METHODS
Using 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.


RESULTS
Cells 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.


CONCLUSIONS
Targeting 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.
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. Oreekha@gmail.com.|Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. Oreekha@gmail.com.
Oreekha
O
Amin
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. marie-claude.beauchamp2@mail.mcgill.|Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. marie-claude.beauchamp2@mail.mcgill.
Marie-Claude
MC
Beauchamp
Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. paulrabounader@gmail.com.
Paul Abou
PA
Nader
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. ido.laskov@mail.mcgill.ca.|Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. ido.laskov@mail.mcgill.ca.
Ido
I
Laskov
Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. sanaa.iqbal@hotmail.com.
Sanaa
S
Iqbal
Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. charles-andre.philip@mail.mcgill.ca.
Charles-André
CA
Philip
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. amber.yasmeen@mail.mcgill.ca.|Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. amber.yasmeen@mail.mcgill.ca.|Department of Oncology, McGill University, Montreal, QC, Canada. amber.yasmeen@mail.mcgill.ca.
Amber
A
Yasmeen
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. walter.gotlieb@mcgill.ca.|Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, QC, Canada. walter.gotlieb@mcgill.ca.|Department of Oncology, McGill University, Montreal, QC, Canada. walter.gotlieb@mcgill.ca.
Walter H
WH
Gotlieb
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D059765:Homologous Recombination; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1