Resistance to chemotherapy is a common finding in the clinic, which limits the efficacy of anti-cancer therapies. Oscar Fernandez-Capetillo, Karolinska Institutet/SciLifeLab, and colleagues, have explored how mammalian cells might become resistant to chemical inhibitors of ATR, a molecule involved in sensing DNA damage.
Using mouse genetics, the group has previously shown that limited ATR activity is particularly toxic for tumors with high levels of replication stress. The group has also developed chemical inhibitors of ATR, which they showed were preferentially toxic for cells expressing oncogenes or lacking p53.
In their latest study, the group conducted a genome wide screening by developing a novel primary mouse embryonic stem cell line that enhances the efficiency of CRISPR-Cas9 mediated mutations. The screening led to the identification of CDC25A deletions in ATR inhibitor resistant cells. Importantly, the authors also identified a combinatorial treatment that can kill the resistant cells, offering an alternative for the treatment of therapy-resistant tumors.
The authors also report that while CDC25A deletions render cells resistant to the treatment, CDC25A overexpression sensitizes cells to these agents. This finding, published in Molecular Cell, is clinically relevant since CDC25A is frequently overexpressed in cancer, and thus might offer a biomarker to identify patients that might particularly benefit from a treatment with ATR inhibitors.