The interplay between DNA damage and autophagy in lung cancer: A mathematical study

The rising mortality in lung cancer, as well as the constraints of the existing drugs, have made lung cancer a major research topic. DNA damage marks the early onset of cancer as it often results from vulnerabilities due to UV rays, oxidative stress, ionizing radiation, and various types of genotoxic attacks. p53 plays an unequivocal role in the DNA repair process and has an abiding presence at the crossroads of the pathways linking DNA damage and cancer. p53 also regulates autophagy in a dual manner based on its cellular localization. The plexus of autophagy regulated by p53 includes AMPK and BCL2, which are positive and negative regulators of prime autophagy inducer beclin1, respectively. Although autophagy is a quintessential process, its levels need to be monitored as uncontrolled autophagy may lead to cell death. The association of p53 and autophagic cell death is very vital as the former acts whenever any threat comes to DNA while the latter may play a role in getting rid of the culprit cell. Therefore, in this paper, we have formulated a seven-dimensional mathematical model connecting p53, DNA damage, and autophagy in lung cancer. We performed both local and global sensitivity analysis along with parameter recalibration analysis to understand the system dynamics. We hypothesized that, by the modulation of beclin1 level, the regulation of AMPK and BCL2 could be a possible strategy to mitigate the progression of lung cancer.

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