Targeting RPS6K1 for Refractory Breast Cancer Therapy

In 2020, female breast cancer overtook lung cancer to become the most diagnosed cancer worldwide. Nearly 30% of women diagnosed with early-stage breast cancer have recurrent disease with resistance to therapeutics evidenced in 25% of cases. The hormone receptor positive (ER+ and PR+) and HER2+ breast cancers quickly develop resistance to the frontline therapeutics, namely, endocrine therapy and trastuzumab treatment. The overactivity of the PI3K/mTOR/S6K1 pathway has been shown to lead to multidrug resistant breast cancer. While PI3K and mTOR targeted therapeutics have shown promise, development of resistance and mutations in these proteins have limited the success of these agents. S6K1 kinase, a downstream effector whose activation leads to translation of ribosomal proteins, enhancement of mRNA biogenesis, and cap-dependent translation and elongation, is a critical player in the PI3K/mTOR pathway and the ER+ pathway. Inhibiting the activity of S6K1 can provide the needed therapeutic option for resistant/refractory breast cancer patients.