The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.

PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance

Vitale S. R.;Martorana F.;Stella S.;Inzerilli N.;Massimino M.;Manzella L.;Vigneri P.
2021-01-01

Abstract

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.
2021
Breast cancer
PI3K
PI3K-inhibitors
PI3K/AKT/mToR pathway
PIK3CA mutations
Female
Humans
Mutation
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
TOR Serine-Threonine Kinases
Breast Neoplasms
Phosphatidylinositol 3-Kinase
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/511252
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