A Perspective of PI3K/AKT/mTOR Pathway Inhibitors to Overcome Drug-resistance in Breast Cancer Therapy.

The heterogeneous disease, breast cancer (BC), is a frequently detected cancer today, including hormone receptor-positive (HR+), human epidermal growth factor receptor-2-positive (HER2+), and triple-negative (ER-, PR-, HER2-) BC. Advanced endocrine therapies could improve about 85% HR+ BC patient survival. Still, 20% - 30% of cases of endocrine therapy resistance are observed. For all kinds of breast cancer, drug resistance is a common and dangerous phenomenon, comprised of two types: de novo resistance and acquired resistance (prolonged exposure). According to recent works of literature, the PI3K/AKT/mTOR pathway has become an emerging target for overcoming drug resistance in BC therapy due to its close association with tumour growth and resistance from current therapies. Activation of the PI3K/AKT/mTOR pathway was found to promote multidrug resistance by elevating drugs' outflow. The first orally active PI3K inhibitor, Alpelisib (BYL-719) in fulvestrant combination, was approved for treating HR+/ HER2- metastatic BC. Therefore, utilizing PI3K/mTOR/AKT inhibitors in combination with currently available strategies could be an optimistic approach to overcoming drug resistance and resensitizing drug-resistant tumor cells of BC. Here, in this perspective, BC cancer therapies related to drug resistance, the involvement of PI3K/AKT/mTOR pathway in drug resistance and multi-drug resistance, and the role of PI3K/AKT/mTOR inhibitors in getting rid of drug resistance have been illuminated.
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