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) displays the most unfavourable prognosis and high risk of recurrence. Conventional chemotherapy and DNA damaging agents are the main treatment for this cancer. However, this tumor subtype is characterized by high heterogeneity and therapy resistance issues, which constantly demands for novel strategies of treatment. Since TNBC presents high m6A methyltransferase METTL3 activity, which correlates with invasiveness and metastasis, we proposed to evaluate the impact of m6A depletion through METTL3 chemical inhibition using STM2457 small-molecule. Here, we show that STM2457, a selective METTL3 catalytic inhibitor, strongly affects TNBC cell proliferation and migration in vitro and in vivo. Moreover, STM2457 sensitizes tumor cells to DNA damaging agents utilized in TNBC therapy, such as platinum-salts and the PARP1/2 inhibitor olaparib. Finally, we show that the catalytic inhibition of METTL3 synergizes with DNA-damaging chemotherapy in TNBC patient-derived organoids with wild-type BRCA1 and BRCA2 genes. Taken together, 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. This approach has the potential to enhance anti-cancer efficacy and mitigate the risk of toxicities.