PI3K/AKT signaling pathway and cancer: an updated review

Figures & data

Figure 1. Overview of PI3K/AKT/mTOR signaling pathway. Class I PI3Ks are activated by growth factors through GPCR or RTK receptors. The PI3K activation results in the conversion of in PtdIns(4,5)P₂ to PtdIns(3,4,5)P₃, a process that is reversed by phosphatase PTEN. PtdIns(3,4,5)P₃ constitutes a docking site for PH-containing proteins (PDK1 and AKT) recruitment and activation. Subsequently, AKT removes the inhibition on the mTOR/Raptor complex (also known as mTORC1), thus leading to mTORC1 activation. Other intracellular pathways also converge on the mTORC1 complex. One of these is constituted by the Ras-dependent LKB1 pathway, altered in Peutz–Jeghers syndrome. Upon LKB1 activation by Ras, this kinase is able to phosphorylate AMPK (AMP-activated protein kinase), that in turn activates mTORC1 inhibitor TSC2. Another mTORC1-converging pathway is mediated by nutrient-regulated Vps34, which acts positively on mTOR/S6K1, thus integrating glucose and amino-acid inputs on the mTOR pathway. PtdIns(3,4,5)P₃ constitutes a docking site also for other kinases such as TEC kinases and small GTPases (P-Rex1/Rac) involved in cell adhesion/migration, actin reorganization, and apoptosis.

Figure 2. Mechanism of action of pharmacological inhibitors in cancer. Schematic representation of PI3K/AKT/mTOR signaling evidencing activating mutations (signed by orange stars) and loss of function mutations (signed by red interdiction symbols), that are often associated with cancer promotion. Since the literature is conflicting about the effects of PI3Kγ mutations on tumors, in this scheme the mutations affecting this isoform are represented by a question mark (in blue). Furthermore, inhibitors against PI3K, mTOR, or MEK/ERK describe the rationale of combinatorial therapies in cancer treatment.

Table I. Summary of genetic alterations in PI3Ks pathway in human cancer.

Isoform	Genetic mutation		Cancer type	Ref.
p110α	mutation	E542K, E545K, H1047R	GBM, breast, CRC, gastric, AML, hepatocellular, and lung	(132)
	amplification		ovarian, cervical, head and neck, squamous cell lung, gastric	(64,65)
p85 (PIK3R1)	mutation		breast, colon, ovarian, GBM, EEC, NEEC	(50)
p110β (PIK3CB)	mutation	E633K	breast	(77)
	amplification		colon	(68)
p110γ	amplification		CML, invasive breast, PDAC	(71)
p110δ	mutation	E1021K	marginal zone lymphoma	(76)
	amplification		AML	(74)
PTEN	mutation	G129E	prostate, GBM, melanoma, endometrial	(47)
	deletion		urothelial	(78)
INPP4B	deletion		breast, ovarian	(47)
SHIP-1 (INPP5D)	mutation		AML	(47)
AKT1	mutation	E17K, Q79K	breast, CRC, ovarian, bladder	(78)
	amplification		gastric	(84)
AKT2	amplification		ovarian, breast, CRC, pancreatic	(133)
AKT3	mutation		sporadic melanomas	(91)

AML = acute myeloid leukemia; CML = chronic myeloid leukemia; CRC = colorectal cancer; EEC = endometrioid endometrial cancers; GBM = glioblastoma multiforme; NEEC = non-endometrioid endometrial cancers; PDAC = pancreatic ductal adenocarcinoma.

Table II. PI3K inhibitors tested in preclinical and clinical models.

	Compound	Isoform selectivity	Cancer type	Clinical trial status	Reference
Isoform specific	GDC-0032	p110α	solid	I-II, solid tumors	(134)
	GSK2636771	p110β	advanced solid	I-IIa, advanced solid cancers with PTEN deficiency	www.clinicaltrials.gov
	IPI-145	p110γ and p110δ	hematological malignancies	I-IIa, advanced hematological malignancies, III CLL, SLL	(135,136)
	CAL-101 (idelalisib)	p110δ	AML, CLL, Hodgkin's and non-Hodgkin's lymphoma, MCL	I-II-III, AML, CLL, Hodgkin's and non-Hodgkin's lymphoma, MCL, MM	(137,138)
	BYL719	p110α	solid, CRC	I-II, advanced solid tumor, CRC	www.clinicaltrials.gov
Pan-class I PI3K	GDC-0941	Class I PI3K	breast, melanomas, MM, non-Hodgkin's lymphoma, NSCLC, ovarian	I-II, breast, non-Hodgkin's lymphoma, NSCLC	www.clinicaltrials.gov
	BKM120	Class I PI3K	breast, CRC, endometrial, GIST, GBM, leukemia, melanoma, NSCLC, pancreatic, prostate	I-II, breast, CRC, endometrial, GIST, GBM, leukemia, melanoma, NSCLC, pancreatic, renal cell, HNSCC, TCC	(139)
	PX866	Class I PI3K	breast, CRC, MM, NSCLC, pancreatic, prostate, ovarian	I-II, CRC, GBM, NSCLC, HNSCC	www.clinicaltrials.gov
	BAY 80-6946	Class I PI3K	advanced solid	I-II, advanced solid cancers	www.clinicaltrials.gov
	XL-147	Class I PI3K	lymphoma, glioblastoma, NCLC, solid, breast	I, lymphoma, glioblastoma, non-small-cell lung cancer, solid tumors; I-II, breast	(140)
Dual PI3K/mTOR	BEZ235	PI3K and mTOR	breast, ovarian	I-II, breast	www.clinicaltrials.gov
	GDC-0980	PI3K and mTOR	Non-Hodgkin’s lymphoma, solid cancers, breast	I, Non-Hodgkin’s lymphoma, solid cancers, breast	www.clinicaltrials.gov
	NVP-BEZ235	PI3K and mTOR	advanced breast	I-II, advanced breast cancer	www.clinicaltrials.gov
	PF-04691502	PI3K and mTOR	advanced solid	I, advanced solid cancers	(141)
mTOR	CCI-779 (temsirolimus)	mTOR	mRCC, solid, refractory diffuse large B-cell lymphoma, breast, mRCC	I, solid tumors; II, refractory diffuse large B-cell lymphoma and breast; III, mRCC	(96–98,108,142)
	RAD-001 (everolimus)	mTOR	advanced breast, pNET, non-malignant kidney and brain, advanced melanoma, CRC, SCLC	I, advanced breast cancer; II, advanced melanoma, CRC, SCLC	(99,130,143–145)
	AZD8055	mTOR	solid	I, solid tumors	(146)
	INK128	mTOR	advanced solid, breast	I, advanced solid tumors; I-II, breast	www.clinicaltrials.gov
	OSI-027	mTOR	solid, lymphoma	I, solid tumor and lymphoma	www.clinicaltrials.gov
AKT	AZD5363	Akt	advanced breast	I-II, advanced breast	(147)
	GDC-0068	Akt	solid	I, solid cancer	www.clinicaltrials.gov
	GSK690693	Akt	lymphoma	I, lymphoma	www.clinicaltrials.gov
	MK-2206	Akt	solid, breast	I, solid cancer and breast	(148)

AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CRC = colorectal cancer; GBM = glioblastoma multiforme; GIST = gastrointestinal stromal tumors; MCL = mantle cell lymphoma; MM = multiple myeloma; mRCC = metastatic renal cell carcinoma; NSCLC = non-small-cell lung carcinoma; pNET = pancreatic neuroendocrine tumor; HNSCC = head and neck squamous cell carcinoma; SCLC = small-cell lung cancer; SLL = small lymphocytic lymphoma.

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