Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review)

Abstract

Abstract. The most common therapeutic approach for many cancers is chemotherapy. However, many patients relapse after treatment due to the development of chemoresistance. Recently, targeted therapies represent novel approaches to destroy cancer cells. The PI3K/PTEN/AKT pathway is a key signaling pathway involved in the regulation of cell growth. Dysregulated signaling of this pathway may be associated with activating mutations of PI3K-related genes. Analyses of these mutations reveal that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we summarize the PI3K/PTEN/AKT pathway genetic alterations in cancer and their potential clinical applications. IntroductionPhosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate phoshoinositides at the D-3 position of the inositol ring generating second messengers that govern cellular activities and promote various biological properties including proliferation, survival, motility and morphology changes. Members of the PI3K family are grouped into three classes according to sequence homology, substrate preference and tissue distribution (1). In terms of regulating cell division and tumorigenesis, the most important PI3K proteins are those that belong to class IA, the catalytic subunit p110α and its associated regulatory subunit p85. In quiescent cells, the regulatory subunit p85 maintains the p110α catalytic subunit in a lowactivity state. Upon growth factor stimulation, the SH2 domain [Rous-sarcoma (src) oncogene homology-2 domain] of the p85 subunit binds to phosphorylated tyrosine in receptor tyrosine kinases or their substrate adaptor proteins. This binding relieves the inhibition of p110α subunit and mediates recruitment of this subunit to the plasma membrane (2). Activation of p110α leads to the production of phosphatidylinositol 3,4,5-triphosphate (PIP3), which recruits adaptor and effector proteins containing a pleckstrin homology domain (PH domain) to cellular membranes including the protein kinase B (PKB/Akt), phosphoinositide-dependent kinase 1 (PDK-1) (3). Once at the membrane PKB/Akt is phosphorylated at Thr308 and Ser473 by PDK1 and the mTORC2 complex, respectively. Once activated PKB/Akt phosphorylates and actives target proteins involved in many different cellular functions, which span cell cycle progression, cell survival, metabolism, ribosome biogenesis, protein translation, RNA transcription and cell motility (4,5

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

“…Evidence from in-vitro and in-vivo models suggests that PI3K-AKT activation is associated with decreased sensitivity to several chemotherapeutic agents and radiotherapy [3, 7]. Additionally, clinical reports highlight the route of resistance to EGFR and HER2 targeted agents, Cetuximab and Trastuzumab (Herceptin), as being reversible upon PI3K-AKT inhibition [98, 99].…”

“…Alteration of upstream pathway components, such as activating mutations in RAS, PI3K or loss of PTEN, can be the primary oncogenic event leading to therapeutic failure[2, 6]. However, it is the activation of AKT that is proposed to modulate cell death responses to therapeutic agents and mediate resistance [3, 7]. Not surprisingly, the aim of regaining sensitivity to various therapies has focused attention on targeting the PI3K-AKT pathway [8].…”

p85α is a microRNA target and affects chemosensitivity in pancreatic cancer

“…Because of its role in cell proliferation and survival, alterations in the PI3K-AKT pathway have been described in various cancers [4]. In addition to its contribution to cancer development and progression, aberrant PI3K-AKT signaling is involved in resistance to various chemotherapeutic agents [5]. PI3K class I A molecules, the only members of this kinase family involved in cancer, consist of a heterodimer comprised of the p110 catalytic and p85 regulatory subunits [3,4].…”

Knockdown ofAKT3(PKBγ) andPI3KCASuppresses Cell Viability and Proliferation and Induces the Apoptosis of Glioblastoma Multiforme T98G Cells

“…The PI3KCA gene has been found to be amplified and overexpressed in several types of cancers. It has been suggested that the point mutations that activate the PI3KCA gene may represent a novel mechanism for the induction oncogenic PI3K signaling pathway [14, 15]. Hafsi et al [15] stressed the fact that oncogenic PI3KCA mutations play a critical role in human malignancies and provide evidence that kinases with cancer-specific mutations such as PI3K may be ideal targets for small-molecule specific inhibitors that would create the opportunity to develop new anticancer drugs [15].…”

“…It has been suggested that the point mutations that activate the PI3KCA gene may represent a novel mechanism for the induction oncogenic PI3K signaling pathway [14, 15]. Hafsi et al [15] stressed the fact that oncogenic PI3KCA mutations play a critical role in human malignancies and provide evidence that kinases with cancer-specific mutations such as PI3K may be ideal targets for small-molecule specific inhibitors that would create the opportunity to develop new anticancer drugs [15]. PI3KCA gene mutations have been found in several cancers (e.g., liver, breast, colorectal, brain, and gastric) and the majority of these have been shown constitutively to activate the protein's catalytic subunit [16, 17].…”