Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

Table 1 Role of Akt in regulating cell cycle

Cell cycle regulation by Akt upon mitogen stimulation
Cell cycle phase	Direct regulation	Indirect regulation	Downstream effect
G1 → S phase	P-p21 at Thr145 residue[107]	↑ Transcription of c-MYC[108]	Increase in CyclinD expression
			Decrease in cdk inhibitors: p21cip1, p21kip1, p15INK4B
G2 → M phase	P-Cdc25B at Ser353[109]		Cdc-25B inactivation
			Cyclin B activation
	P-Wee1Hu at Ser642[110]		Inactivation of Wee1Hu results in G2/M cell cycle progression
	P-Myt1 at Ser75[111]		Activation of Cyclin B-associated Cdk1 kinase activity
S → G2 phase	P-Cdk2 at Thr39[112]		Cytoplasmic shuttling of Cdk2

Table 2 Summary of phosphatidylinositol-3 kinases/Akt/mTOR inhibitors under investigation for gastric cancer treatment

Classification of PI3K/Akt/mTOR inhibitors	Inhibitors under investigation for GC	Clinical status for GC
PI3K inhibitors: 3 classes of PI3K inhibitors
Pan-class I inhibitors	PX-866	Phase-II study for solid tumors
	NVP-BKM120	Phase-I study for advanced solid tumors
	ZSTK474	Preclinical studies
	BAY80-6946	Phase-II study for advanced solid tumors
Isoform specific PI3K inhibitors	BYL719	Phase-I study
	INK117	Phase-I study
Dual Akt/mTOR inhibitors	NVP-BEZ235	Preclinical studies
	VS-5884	Phase-II study
	PI-103	Phase-I study
Akt inhibitors	AZD5363	Preclinical studies
	MK-2206	Phase-II study
	Perifosine	Preclinical studies
	TCN-PM	Phase-I study for solid tumors
mTOR inhibitors: 2 types
Rapalogs	Everolimus	Phase-III study
	Ridaforolims	Preclinical studies
	Sirolimus	Phase-I study
	Temsirolimus	Phase-II study
mTORC1/2 inhibitors	PP242	Preclinical studies

GC: Gastric cancer; PI3K: Phosphatidylinositol-3 kinases.