PKMYT1 inhibitors (Iktos)

ATIP3-deficient breast cancers represent a subset of aggressive tumors with limited therapeutic options and poor prognosis. Here, we screened a panel of cell cycle kinase inhibitors to identify novel targets for these tumors. We show that loss of ATIP3 sensitizes breast cancer cells to WEE1 inhibition, resulting in aberrant mitoses characterized by detachment of centromere proteins from DNA and chromosome pulverization. This phenotype arises from excessive replication stress and DNA damage in S-phase, combined with premature mitotic entry driven by untimely CDK1 activation. Mechanistically, we identify DNA2 helicase/nuclease as a key mediator of chromosome pulverization. Importantly, the heightened sensitivity of ATIP3-deficient cells to WEE1 inhibition provides a strong rationale for clinical exploration of WEE1-targeted therapies. Furthermore, combining WEE1 and PKMYT1 inhibitors enhances therapeutic efficacy, offering a promising strategy for personalized treatment in ATIP3-deficient breast cancers.