Fig. 7: Schematic model of targeting CCNE1 amplified cancers with dual inhibition of PKMYT1 and ATR.
From: Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR
A, B Model of synergy between PKMYT1 and ATR inhibition in CCNE1-amplified or overexpressing cells. A CCNE1 amplification or overexpression in cells causes replication stress and S-phase elongation. To delay induction of mitosis until DNA replication is complete, CDK1 activity is inhibited by increased PKMYT1 inhibitory phosphorylation on CDK1-Thr-14 and decreased CDC25 phosphatase activity via ATR-CHK1 signaling. B Inhibition of PKMYT1 (lunresertib) reduces CDK1 The14 phosphorylation and inhibition of ATR (camonsertib) increases CDC25 activity resulting in rapid and robust S-phase CDK1 activation and premature mitosis with synergistic induction of DNA damage and cell death.
