Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer

Abstract

Recently many therapeutic classes have emerged in advanced hormone receptor-positive breast cancer, which is the leading cause of cancer death in women. In absence of visceral crisis, treatment relies on endocrine therapy combined with cyclin dependent kinase 4 and 6 inhibitor. Many mechanisms lead to resistance to endocrine therapy, including the activation of intracellular signaling pathways critical for cell survival. Approximately 70% of breast tumors harbor an alteration in the phosphoinositide 3 kinase (PI3K)/Akt pathway, leading to its hyper activation. This pathway is involved in the regulation of growth, proliferation and cell survival as well as in angiogenesis and is consequently a major target in the oncogenesis. An aberrant PIK3CA mutation is a common phenomenon in breast cancer and found in approximately 40% of patients with advanced hormone receptor-positive breast cancer. For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).

The Role of mTOR Signaling as a Therapeutic Target in Cancer

“…According to the published data, the PI3K/AKT/mTOR pathway is activated in approximately 70% of ovarian or breast cancers [ 88 , 89 ]. For instance, the aberrant activation of the PI3K/AKT/mTOR pathway has been found in 90% of lung adenocarcinomas (ADCs) and 40% of squamous cell carcinomas (SCCs) [ 90 ].…”

Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2

“…V-ATPase regulates the extracellular environment of tumor cells and the pH of many intracellular compartments, thus enabling tumor cells to maintain a high metabolic rate and contributing to their autophagy, invasion, migration and drug resistance [ 5 , 29 ]. Enhanced phosphoinositide 3-kinase/AKT/mTOR signaling has been associated with BC and found to promote drug resistance [ 30 ]. Everolimus, which inhibits mTORC1 and induces AKT phosphorylation, has been approved for the treatment of postmenopausal women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced BC [ 31 ].…”

QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis

“…Through human proteome microarray, co-IP, immunofluorescence staining and confocal laser microscopy observation, the present study found that QPCT bound to PIK3CA, and PI3K/Akt/mTOR was one of the main intracellular signaling pathways. PI3K signals regulate various cellular functions, including translational regulation of cell proliferation, survival, protein synthesis, glucose metabolism, cell migration and angiogenesis (39)(40)(41)(42)(43). The disruption of this pathway leads to a range of diseases, including cancer (44).…”