Allosteric inhibition of ABL kinases: therapeutic potential in oncofertility

Cancer treatments, although effective, often carry out a significant risk of premature ovarian insufficiency (POI) and infertility, particularly affecting the life quality of young patient. Mitigating this risk is critical and requires proactive discussions to refer patients to reproductive specialists to preserve ovarian function and fertility. Comprehensive oncofertility counselling requires an understanding of the treatment-induced POI risks associated with different cancer treatments. Emerging data highlights the pivotal role of the non-receptor tyrosine kinase c-Abl in depleting ovarian reserve following exposure to chemotherapeutic agents. Previous experiments in mice demonstrate that pharmacological inhibition of c-Abl significantly mitigates adverse effects caused by common chemotherapeutic agents such as cisplatin and cyclophosphamide. In this study, we explored the impact of the allosteric inhibitor of c-Abl, Asciminib, known for minimizing chemotherapeutic side effects without affecting multiple kinases. By investigating two different ovarian cancer cell lines (OVCA433 and OVCAR3) as well as human cumulus cells, our research aimed to elucidate the potential role of c-Abl inhibitors in human oncofertility. The results provided new insights into the impact of c-Abl inhibitors on human oncofertility and identified novel molecular targets that could alleviate the side effects of cancer treatments in human cumulus cells. In addition, our findings support the repurposing of Asciminib, an FDA-approved drug for patients with chronic myeloid leukemia (CML), by providing evidence of its potential anti-tumor effects in ovarian cancer cells.