Abstract
Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.
Highlights
The epidermal growth factor receptor (EGFR) plays an essential role in carcinogenesis by modulating proliferation, differentiation, and the DNA damage response [1,2,3,4,5]
Consistent with our hypothesis, we demonstrate that C225 augments cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells by enhancing the intrinsic apoptotic pathway
Cetuximab enhances cytotoxicity with PARPi We have previously demonstrated that C225, the anti-EGFR
Summary
The epidermal growth factor receptor (EGFR) plays an essential role in carcinogenesis by modulating proliferation, differentiation, and the DNA damage response [1,2,3,4,5]. EGFR has become heavily targeted as a cancer therapeutic strategy, and this has improved response rates, locoregional control, and overall survival in combination with radiation in head and neck cancer patients [2,7]. Almost half of head and neck cancer patients treated with this strategy will still succumb to this disease. PARPi has been reported to enhance cytotoxicity in sporadic tumors when combined with other DNA damaging agents, such as with platinum and cyclophosphamide in breast cancer and with temozolomide in glioblastoma [11]. Much effort has been undertaken to expand the utility of PARPi beyond the realm of BRCA-associated tumors by combining with agents that alter the DNA damage/repair pathways
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