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

Table 1 Molecular biomarkers associated with the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway in triple negative breast cancer

Biomarkers class	Biomarkers name	Mechanism of action/inhibition	Ref.
Protein biomarkers	TYMS	Knockdown of TYMS leads to downregulation of mTOR, p-PI3K, and p-AKT expressions, inhibits cell proliferation and migration, while promoting apoptosis	[20]
	GBP2	GBP2 overexpression collaborates with autophagy-related protein 2 to inhibit the PI3K/Akt/mTOR pathway, thereby enhances the sensitivity of TNBC cells to paclitaxel	[29]
	ACTL8	Facilitate the proliferation, migration, and invasion of TNBC cells by activating the PI3K/Akt/mTOR signaling pathway while suppressing apoptosis	[30,31]
	OPN	Activate PI3K/Akt/mTOR pathway to regulate anti-lipid peroxidation mediated by GPX4, thereby promoting tumor growth and metastasis in TNBC	[38]
mRNA biomarkers	ROR2	Downregulation of ROR2 augments chemical sensitivity towards adriamycin; upregulation of ROR2 activates the PI3K/Akt/mTOR signaling pathway to facilitate TNBC metastasis	[43]
Non-coding RNA markers	Linc00707	Competitively bind to miR-423-5p to up-regulate MARCH2 expression, promote TNBC progression and autophagy through the PI3K/Akt/mTOR pathway	[45]
	MiR-145	Decreasing in miR-145 attenuates PI3K activation by inhibiting the MAPK signaling pathway, thereby diminishing AKT and mTOR activity	[48]
Transcription factor	Nrf3	The overexpression of Nrf3 activates the PI3K/Akt/mTOR signaling pathway and regulates the expression of proteins associated with EMT	[23]

TYMS: Thymidylate synthase; GBP2: Guanylate-binding protein 2; ACTL8: Actin-like protein 8; OPN: Osteopontin; ROR2: Receptor tyrosine kinase-like orphan receptor 2; Nrf3: Nuclear factor erythroid-2-like factor 3; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; TNBC: Triple negative breast cancer; GPX4: Glutathione peroxidase 4; MARCH2: Membrane-associated RING finger protein 2; MAPK: Mitogen-activated protein kinase; EMT: Epithelial-mesenchymal transition.

Table 2 Natural products targeting the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway in triple negative breast cancer

Natural product class	Natural product name	Mechanism of action/inhibition	Ref.
Flavonoids	Prenylated xanthones	Decrease the levels of PI3K, AKT, and mTOR in both total protein and phosphorylated forms	[75]
	Ononin	Reverse EMT through down-regulation of EMT markers and matrix metalloproteinases, attenuate EGFR phosphorylation and inhibit the PI3K/Akt/mTOR pathway	[76]
	Myricetin	Inhibit the PI3K/Akt/mTOR pathway to enhance the anti-cancer efficacy of Myricetin	[77]
	Quercetin	Decrease cell viability, colony formation, angiogenesis, and increase apoptosis. Inhibit the activation of IGF1R and its downstream kinases AKT and ERK1/2. Suppress E-mediated proliferation and migration of TNBC cells by blocking β2-AR/ERK1/2 pathway	[78,80,81]
Terpenoids	PAB	Induces apoptosis through mitochondrial apoptosis and the PI3K/Akt/mTOR pathway	[87]
	Ezhu	Inhibit the proliferation, invasion, migration, and EMT of MDA-MB-231 cells through the PI3K/Akt/mTOR signaling pathway	[89]
	Tan IIA	Enhance the antitumor efficacy of doxorubicin by interfering with the PI3K/AKT/mTOR signaling pathway and inhibiting topoisomerase II	[79]
Alkaloids	RTEs	Enhance the sensitivity of resistant TNBC cells to Taxol through their inhibitory effect on PI3K/Akt/mTOR-mediated autophagy. Suppress MDA-MB-468/Taxol cells autophagy and reduce tumor growth	[91]
	BJE	Inhibit the proliferation, induce apoptosis, and promote the phosphorylation of mTOR, PI3K, and Akt in MDA-MB-231 TNBC cells	[68]
	PIP	Suppress the pro-survival AKT pathway and induce caspase-dependent apoptosis via the mitochondrial pathway. Impair the in vitro migratory capacity of TNBC cells and reduce MMP-2 and MMP-9 mRNA expression. The combination of doxorubicin and PIP can increase necrosis while downregulating PTEN, inhibiting PI3K levels, and the immunoreactivity of p-Akt, mTOR, and ALDH-1	[98,99]
	BBM	Impede TNBC development through regulation of the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signaling pathways	[100]
	HHT	Downregulate p-AKT, p-mTOR, and Bcl-2 expression, while upregulating TP53, Bax, cleaved caspase-3, and caspase-9 expression, and inhibiting the PI3K/AKT/mTOR pathway	[101]

PAB: Pseudolaric acid B; Tan IIA: Tanshinone IIA; RTEs: Radix tetrastigma extracts; BJE: Brucea javanica seed; PIP: Piperine; BBM: Berbamine; HHT: Homoharringtonine; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; EMT: Epithelial-mesenchymal transition; EGFR: Epidermal growth factor receptor; IGF1R: Insulin-like growth factor-1 receptor; ERK: Extracellular signal-regulated kinase; TNBC: Triple negative breast cancer; MMP: Matrix metalloproteinase; PTEN: Phosphatase and tensin homolog; PIP: Piperine; MDM2: Murine double minute 2; ALDH-1: Aldehyde dehydrogenase-1.

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.

Table 4 Ongoing clinical trials associated with the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin pathway in triple negative breast cancer

Inhibitors class	Trial code	Trial content	Trial period
mTOR inhibitors	NCT02616848	A phase I clinical trial to evaluate the efficacy and safety of everolimus in combination with arebuline for previously treated mTNBC	I
Pan-PI3K inhibitors	NCT01790932	A phase II clinical trial evaluating the efficacy of monotherapy with buparlisib (BKM120) in patients with TNBC	II
Pan-PI3K inhibitors	NCT01629615	A phase II clinical trial evaluating the efficacy of monotherapy with buparlisib in patients with TNBC	II
PI3K inhibitors	NCT02389842	A phase Ib clinical trial assessing the efficacy and safety of taselisib, a beta-preserving PI3K inhibitor, in combination with palbociclib for metastatic breast cancer, including those with TNBC	Ib
PI3K inhibitors	NCT03207529	A phase I clinical trial evaluating the combination of alpelisib, an alpha-specific PI3K inhibitor, with enzalutamide in patients with AR+ and PTEN+ breast cancer, including those with TNBC	I
AKT inhibitors	NCT02576444	A phase II clinical trial investigated various combinations of olaparib, specifically focusing on patients with breast cancer who received both olaparib and capivasertib	II
AKT inhibitors	CAPITELLO290	A clinical trial of the capivasertib in combination with paclitaxel for first-line treatment in patients with locally advanced or metastatic TNBC, included evaluating OS in subgroups whose tumors harbored PIK3CA, AKT1, or PTEN biomarker alterations	III

PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; mTNBC: Metastatic triple-negative breast cancer; TNBC: Triple negative breast cancer; PTEN: Phosphatase and tensin homolog; AR: Androgen receptor; OS: Overall survival; PIK3CA: Phosphoinositide3 kinase-alpha.