Breast cancer, which affects approximately one in eight women worldwide, remains a heterogeneous disease, with some forms—particularly so-called triple-negative cancers—still carrying a poor prognosis. Among the markers identified for these tumors, the microtubule-stabilizing protein ATIP3 plays a prognostic role: its decrease, observed in 50 to 80% of breast cancers and especially frequent in triple-negative forms, is associated with increased aggressiveness and reduced survival. ATIP3-deficient tumors are characterized by marked aneuploidy and chromosomal instability. Although taxanes such as paclitaxel exploit this vulnerability, their clinical use remains limited by their toxicity and by the fact that they benefit only about 30% of patients, hence the need for better-targeted therapies.
To address this challenge, the authors screened a panel of cell-cycle kinase inhibitors in order to identify novel targets specific to these tumors. This work shows that ATIP3 loss sensitizes breast cancer cells to inhibition of the WEE1 kinase. This sensitization manifests as aberrant mitoses, marked by the detachment of centromeric proteins from DNA and by chromosome shattering.
Mechanistically, this phenotype results from the conjunction of two phenomena: excessive replication stress accompanied by DNA damage during S phase, and premature mitotic entry caused by untimely activation of the CDK1 kinase. The researchers identify the helicase/nuclease DNA2 as a key mediator of chromosome shattering. The characterization of these events thus clarifies the molecular basis of the particular vulnerability of ATIP3-deficient cells.
The increased sensitivity of these cells to WEE1 inhibition provides strong support for the clinical exploration of therapies targeting this kinase. Furthermore, the authors establish that combining WEE1 and PKMYT1 inhibitors enhances therapeutic efficacy. This combination represents a viable strategy for the personalized treatment of ATIP3-deficient breast cancers, in line with a precision medicine approach tailored to the molecular vulnerabilities of these tumors.