Fig. 5
From: Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation
Major DDR inhibitor drug resistance mechanisms. DDR inhibitor resistance can be acquired or inherent. ATR inhibitor resistance is determined by the PGBD5 depletion and CDC25A deficiency. DNA-PK inhibitor resistance is caused by the loss of MLH1/MSH3 and the overexpression of ABCG2. WEE1 inhibitor resistance is induced by AXL overexpression, mTOR signaling, and CHK1 activation; the overexpression of MYT1 levels lowers CDK1 activity and contributes to WEE1 inhibitor resistance. CHK1 inhibitor resistance is associated with increased E2F/G2M/SAC expression and reduced replication stress. DDR DNA damage response, PARP poly(ADP-ribose) polymerase, PARG poly(ADP-ribose) glycohydrolase