Dottorato in MORFOGENESI E INGEGNERIA TISSUTALE

Titolo della tesi: Enhancing sensitivity of triple-negative breast cancer to DNA damaging therapy through chemical inhibition of the m6A methyltransferase METTL3

Among the different types of breast cancer, triple-negative breast cancer (TNBC) is the one with the most unfavourable prognosis and high risk of recurrence. Conventional chemotherapy and DNA damaging agents represent the main treatment for this cancer. TNBC is characterized by high METTL3 methyltransferase activity, and this correlates with invasiveness and metastasis. Here, we show that STM2457, a selective METTL3 catalytic inhibitor, strongly affect TNBC cells proliferation and migration in vitro and in vivo. Moreover, STM2457 strongly sensitizes TNBC cells to DNA damaging agents utilized in clinics, such as platinum-salts and the PARP1/2 inhibitor olaparib. Finally, we show that the catalytic inhibition of METTL3 significantly synergizes with DNA-damaging chemotherapy and PARP inhibitor in TNBC BRCA1/2-wild-type organoids. In conclusion, our data suggests that incorporating small-molecule inhibitors of METTL3 into standard treatment for TNBC holds significant promise, opening avenues for innovative combination targeted therapies. Indeed, this approach has the potential to enhance anti-cancer efficacy and mitigate risk of toxicities.