Patients with triple-negative breast cancer (TNBC), an aggressive subtype, currently have limited options and generally face a poor prognosis. Researchers led by Khandan Keyomarsi, Ph.D., Mi Li, Ph.D., and Amriti Lulla, Ph.D., discovered that increased levels of low molecular weight cyclin-E (LMW-E) and cyclin-dependent kinase (CDK1) phosphorylation are associated with poor outcomes following chemotherapy. High levels of LMW-E and CDK1 predicted the poorest treatment responses, suggesting they serve as potential biomarkers of chemotherapy resistance.
The study showed that LMW-E upregulates and stabilizes PKMYT1, leading to enhanced CDK1 phosphorylation. TNBC cells with high LMW-E levels were more sensitive to the PKMYT1 inhibitor RP-6306, which induces DNA damage and mitotic arrest. Treatment with RP-6306 also led to tumor suppression, increased DNA damage and extended survival in vivo, using both patient derived xenograft and transgenic models. These findings highlight the therapeutic potential of PKMYT1 inhibitors for patients with TNBC.