fig2

Figure 2. Adaptation of cancer cells to oxidative stress. Activation of the RAS or PI3K pathway leads to elevated production of reactive oxygen species (ROS), which causes oxidative DNA damage and, ultimately, cellular senescence. Two modes of adaptation have been described to enable cancer cells to avoid cellular senescence and continue to proliferate. Some cancer cells increase their antioxidant capabilities notably following genetic inactivation of the Kelch-like ECH-associated protein 1 (KEAP1) gene which leads to nuclear factor erythroid-2 related factor 2 (NRF2) upregulation and the subsequent transcriptional activation of antioxidant genes. Alternatively, some cancer cells increase their BER capacities by overexpressing BER enzymes such as Pol β, APE1, and FEN1 or auxiliary factors such as CUX1, CUX2, or SATB1. As a by-product of increased BER activity, these cancer cells exhibit resistance to genotoxic treatments like radiation therapy(IR), temozolomide (TMZ), cisplatin, or methyl methanesulfonate (MMS).