Inhibition of Both EGFR and IGF1R Sensitized Prostate Cancer Cells to Radiation by Synergistic Suppression of DNA Homologous Recombination Repair

Abstract

Reduced sensitivity of prostate cancer (PC) cells to radiation therapy poses a significant challenge in the clinic. Activation of epidermal growth factor receptor (EGFR), type 1 insulin-like growth factor receptor (IGF1R), and crosstalk between these two signaling pathways have been implicated in the development of radiation resistance in PC. This study assessed the effects of targeting both receptors on the regulation of radio-sensitivity in PC cells. Specific inhibitors of EGFR and IGF1R, Erlotinib and AG1024, as well as siRNA targeting EGFR and IGF1R, were used to radio-sensitize PC cells. Our results showed that co-inhibiting both receptors significantly dampened cellular growth and DNA damage repair, and increased radio-sensitivity in PC cells. These effects were carried out through synergistic inhibition of homologous recombination-directed DNA repair (HRR), but not via inhibition of non-homologous end joining (NHEJ). Furthermore, the compromised HRR capacity was caused by reduced phosphorylation of insulin receptor substrate 1 (IRS1) and its subsequent interaction with Rad51. The synergistic effect of the EGFR and IGF1R inhibitors was also confirmed in nude mouse xenograft assay. This is the first study testing co-inhibiting EGFR and IGF1R signaling in the context of radio-sensitivity in PC and it may provide a promising adjuvant therapeutic approach to improve the outcome of PC patients to radiation treatment.

Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors

“…DNA damage and enhanced DNA repair [41]. Inhibition of IGF-1R resulted in the delayed repair of radiation-induced DNA doublestrand breaks, potentiating the antiproliferative effect of radiation therapy [42,43]. IGF-1R signaling was also involved in resistance to conventional chemotherapy [44,45].…”

LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

“…Of note, IGF1R can physically associate with EGFR, and the ligands EGF and IGF1 can activate both EGFR and IGF1R even when the two receptors are not physically connected (58)(59)(60)(61). Since LMP1 regulates activation of EGFR and IGF1R, it is possible that LMP1 promotes interaction between these receptors to facilitate their phosphorylation.…”

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

“…These structural homologous receptors are recognized for tumor cell regulation of proliferation, survival, apoptosis, and angiogenesis [28, 29] making these two receptors favorable targets for cancer therapy [24, 29, 30]. Recent studies have shown IGF1R mainly mediates via the PI3K/AKT pathway while the EGFR mediates through the Ras/MAP kinase pathway [31, 32].…”

“…Multiple studies have shown selective inhibition of one receptor will lead to compensatory and enhanced activation of the other receptor axis [29, 33, 34]. These cellular and molecular mechanistic observations have led to research on specific targeted therapy for dual inhibition of EGFR and IGF1R [28–30, 35]. …”