Fig. 3

Synthetic lethality with mutp53 LOF and GOF. A Wtp53 maintains the survival-promoting pathways when cells undergo stress. Mutp53 loses these functions but activates compensatory pathways to protect cancer cells from lethal stresses. Thus, these compensatory pathways become vulnerable in cancers as these pathways are less dependent on normal cells. Taking the role of p53 in cell cycle arrest as an example, in response to DNA damage, wtp53 can activate p21 to induce G1 arrest to repair DNA damage (left). Under conditions of p53 mutation, cancer cells rely more on S and G2 arrest for DNA repair. Inhibition of regulators of S and G2 arrest results in the accumulation of unpaired DNA and mitotic catastrophe (right). B For mutp53 GOFs, the target genes upregulated by mutp53, which are usually silenced when p53 is not mutated, might be the crucial factors promoting tumor progression. Targeting these genes can selectively suppress the cancer progression of cancers with mutp53. Regarding energy metabolism, wtp53 inhibits glycolysis and promotes OXPHOS (left), and mutp53 acquires the opposite functions to promote glycolysis and inhibit OXPHOS (right). Herein, targeting the enhanced glycolysis induced by mutp53 can be developed for synthetic lethal approaches