Explore PI3K/AKT

PI3K plays a role in cell signaling and membrane trafficking¹⁶

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P₂=phosphatidylinositol 4,5-bisphosphate; PIP₃=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

Each of the 3 classes of phosphatidylinositol 3-kinases (PI3Ks) has its own substrate specificity, tissue distribution, and mechanism of action.^17,18 Class I PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PI4,5P₂) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP₃), which mediates AKT activation.⁵

Class I PI3Ks, which are present in all cell types, are comprised of 4 isoforms: p110α, p110β, p110δ, and p110γ.^16,19 Although the 4 isoforms serve distinct functions based on cellular context (eg, p110δ and p110γ are mainly restricted to function in leukocytes), their activation leads to the production of PIP₃, which mediates AKT activation through membrane recruitment by binding to its pleckstrin homology (PH) domain.^5,16

Somatic mutations in p110α have been identified in a variety of cancer types.¹⁷ These mutations increase kinase activity and contribute to transformation.²⁰ Mutations in phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), the gene coding for p110α, are prevalent in a diverse variety of cancer types, making PIK3CA the most commonly mutated oncogene.²⁰

Cancer types with a high prevalence of PIK3CA mutation include liver, breast, and colorectal.²¹ The PI3K signaling pathway is altered in the majority of patients with advanced-stage prostate cancer, with biallelic loss of the tumor suppressor phosphatase and tensin homolog (PTEN) being the most common somatic mutation.¹⁴

PI3K inhibition may block the growth of tumors activated by oncogenic receptor tyrosine kinases (RTKs), PI3K mutants, and/or PTEN loss of function. Inhibition strategies include adenosine triphosphate (ATP)-competitive pan-PI3K selective inhibitors, isoform-specific PI3K inhibitors, and inhibitors targeting isoform-specific PI3K mutations.^13,20

PTEN controls AKT signaling and serves as a tumor suppressor²²

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P₂=phosphatidylinositol 4,5-bisphosphate; PIP₃=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

Phosphatase and tensin homolog (PTEN) acts as a negative regulator of the PI3K/AKT pathway through its ability to convert phosphatidylinositol 3,4,5-trisphosphate (PIP₃) to phosphatidylinositol 4,5-bisphosphate (PI4,5P₂).^5,22 Inactivating mutations or loss of heterozygosity in PTEN can lead to the hyperactivation of AKT signaling and increase the risk of cancer development.⁵

Germline mutations in PTEN have been described in a number of syndromes collectively known as PTEN hamartoma tumor syndrome (PHTS).²² Patients with PHTS have an increased incidence of breast, thyroid, and endometrial cancers, and PTEN is among the most commonly mutated tumor-suppressor genes in sporadic cancer. It has also been implicated in the development of multiple cancer types, including prostate, breast, endometrium, thyroid, central nervous system, lung, pancreas, liver, and adrenal glands. Additionally, it has been involved in cases of melanoma, leukemia, and lymphoma.²²

AKT signaling is crucial in cellular processes and often dysregulated in many cancers^5,23

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P₂=phosphatidylinositol 4,5-bisphosphate; PIP₃=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

AKT is the central node of the PI3K/AKT pathway and has an essential regulatory role in multiple cellular processes.^23,24 There are 3 highly homologous AKT isoforms (AKT 1, AKT 2, and AKT 3) that are encoded by separate genes and share over 80% amino acid sequence identity in mammalian cells.²⁵

AKT is one of the most frequently activated protein kinases in human cancers. Hyperactivation of AKT may induce cell growth, lead to cell proliferation, and contribute toward resistance to apoptosis.²⁵

In cancer, AKT activity is frequently elevated due to oncogenic growth factors, angiogenic factors, cytokines, and genetic alterations, including mutations and/or amplifications of the AKT1, AKT2, and AKT3 genes; loss of function of the phosphatase and tensin homolog (PTEN) tumor-suppressor; and mutations of the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) gene.¹⁵ Inactivation of PTEN and missense alleles of PIK3CA have been associated with constitutive activation of AKT. AKT activation has been correlated with various clinicopathologic parameters such as advanced disease and/or poor prognosis in a number of tumors.²⁶

The oncogenic potential of the AKT pathway is further supported by the fact that a murine model-based conditional PTEN deletion, leading to increased activation of AKT signaling, may result in the development of metastatic cancer.¹⁴ Ectopic expression of constitutively active AKT resulted in oncogenic transformation, both in vitro and in vivo. In addition, downregulation or knockdown of AKT by antisense or small interfering ribonucleic acid (siRNA) significantly reduced tumor growth and invasiveness, as well as induced apoptosis and cell growth arrest only in tumor cells overexpressing AKT.¹⁵

PI3K/AKT Upregulation

Preclinical data suggest that the PI3K/AKT pathway may be upregulated as a result of targeting other signaling pathways.^12,14,27

• The PI3K/AKT pathway has been implicated as a key player in the development of resistance to endocrine therapy¹²
• The activation of the PI3K/AKT pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types¹²
• Repression of the androgen receptor in prostate cancer was shown in preclinical models to induce AKT activity, indicating the existence of a reciprocal feedback mechanism^14,27
• It has been reported that many tumors upregulate AKT in order to acquire resistance to standard chemotherapies and targeted therapies²
• Inhibition of mammalian target of rapamycin complex (mTORC) 1 resulted in the upregulation of the AKT pathway, indicating the existence of a feedback loop²⁸

Approaches that include targeting the PI3K/AKT pathway in combination with other treatment modalities may be viable strategies to address resistance mechanisms.^12,14,27