Treatment strategies targeting the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin pathway against triple-negative breast cancer

Table 3 Existing inhibitors targeting the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway in triple negative breast cancer

Inhibitors class		Inhibitors name	Mechanism of action/inhibition	Ref.
PI3K inhibitors	Pan-PI3K inhibitors	Buparlisib (BKM120)	Block hormone receptor-mediated repair through the PI3K/AKT/NF-κB/c-Myc signaling pathway as well as the PI3K/AKT/FOXM1/Exo1 signaling pathway	[102]
	Selective PI3K inhibitors	LY294002	Suppress the expression of PI3K, AKT, and mTOR as well as phosphorylated protein levels activation in TNBC cells while inducing alterations in multi-kinase phosphorylation	[104]
		Inavolisib (GDC-0077)	Inhibit PI3K signaling as well as reduce cell viability through p110α degradation	[106,107]
mTOR inhibitors		AZD8055	Inhibit the proliferation of breast cancer cells, inhibit glycolysis and reduce glucose consumption. Inhibit MEK1/2 activated AKT, cell cycle progression and cell proliferation	[116,117]
Dual PI3K/mTOR inhibitors		BEZ235	Inhibit HIF-1alpha expression and the PI3K/mTOR signaling pathways, induce autophagy, and prolong DNA damage repair. Suppress cell proliferation, migration, and colony formation; promote the degradation of mutant p53	[120,122]
		SF1126	Suppresses tumorigenesis and angiogenesis in vivo. Induce apoptosis by inhibiting the EGFR-PI3K/AKT/mTOR pathway	[123]
		GDC-0084	Reduce the activity of PIK3CA mutant BC BMS cell lines in vitro, induce apoptosis, and inhibit the phosphorylation of AKT and p70S6	[124]
		Gedatolisib	Stimulate the response of dendritic cells, CD8+ T cells, and natural killer cells	[125]
		GDC-0980	Induce DNA damage, inhibit proliferation signaling, upregulate the expression of apoptotic markers, and suppress tumor growth	[127]
AKT inhibitors		Ipatasertib (GDC-0068)	Bind to three subtypes of AKT, thereby inhibit AKT activity, obstruct the PI3K/AKT/mTOR signaling pathway, and diminish tumor cell proliferation and survival	[134,136]
		MK-2206	Inhibit Akt phosphorylation and induct DNA damage	[139]
		Capivasertib (AZD5363)	Reduce stemness and re-sensitize BCSCs to chemotherapeutic agents by modulating mitochondrial fusion	[129]

PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor-kappa B; FOXM1: Forkhead box M1; TNBC: Triple negative breast cancer; HIF: Hypoxia-inducible factor; EGFR: Epidermal growth factor receptor; BCSC: Breast cancer stem cell; PIK3CA: Phosphoinositide3 kinase-alpha.