NF-kB oscillation profiles decode response to anti-EGFR monoclonal antibodies

Abstract

A direct connection between an inflammatory environment and cancer has been extensively proven over the years. We previously reported that the presence of interleukin 1 (IL-1) is responsible for the lack of response to monoclonal antibody targeting epidermal growth factor receptor (EGFR) in colorectal cancer (CRC).

Considering the driver role of NF-kB in controlling the expression of IL-1, herein, we investigate the dynamics of the oscillatory profile of the NF-kB response to monoclonal antibody, on the background of an inflammatory environment. NF-kB is a typical transcription factor that displays intrinsic oscillatory behavior, whose biological relevance in term for example of decoding response to monoclonal antibodies, remains unclear.

Using live cell luciferase techniques, we recorded NF-kB activity over time in response to cetuximab (CTX) alone or in combination with IL-1 cytokines. Our results revealed an additive effect of these two agents on NF-kB activation, which was specific to CTX responsive cells. In contrast, CTX resistant cells did not display a significant change in the NF-kB profile under the IL-1 plus CTX combination. These results suggest an immediate interactive crosstalk between IL-1 and EGFR in the activation of NF-kB signaling pathway, which may lay the basis for the development of drug tolerant persister cells (DTP), leading to CTX resistance.