Amplification of oxidative stress can be utilized as a strategy to attenuate cancer progression by instigating apoptosis. However, the duration of positive response to such therapies is limited, as cancer cells eventually develop resistance. The underlying molecular mechanisms of cancer cells to escape apoptosis under oxidative stress is unknown. Employing big data, and its integration with transcriptome, proteome and network analysis in six cancer types revealed system-level interactions between DNA damage response (DDR) proteins, including; DNA damage repair, cell cycle checkpoints and anti-apoptotic proteins. Cancer system biology is used to elucidate mechanisms for cancer progression, but networks defining mechanisms causing resistance is less explored. Using system biology, we identified DDR hubs between G1-S and M phases that were associated with bad prognosis. The increased expression of DDR network was involved in resistance under high oxidative stress. We validated our findings by combining H2O2 induced oxidative stress and DDR inhibitors in human lung cancer cells to conclude the necessity of targeting a 'disease-causing network'. Collectively, our work provides insights toward designing strategies for network pharmacology to combat resistance in cancer research.
Keywords: A549 cell line; DDR module; DNA damage response; Hubs; Inhibitors; Network biology; Oxidative stress; Resistance.
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