The PI3-K/AKT-Pathway and Radiation Resistance Mechanisms in Non-small Cell Lung Cancer

Abstract

The phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with all three major radiation resistance mechanisms: intrinsic radiosensitivity, tumor cell proliferation, and hypoxia. In cell signaling cascades, the PI3-K/AKT signaling pathway is a key regulator of normal and cancerous growth and cell fate decisions by processes such as proliferation, invasion, apoptosis, and induction of hypoxia-related proteins. Activation of this pathway can be the result of stimulation of receptor tyrosine kinases such as epidermal growth factor receptor or vascular endothelial growth factor receptor or from mutations or amplification of PI3-K or AKT itself which are frequently found in non-small cell lung cancer (NSCLC). Furthermore, several treatment modalities such as radiotherapy can stimulate this survival pathway. Monitoring and manipulation of this signal transduction pathway may have important implications for the management of NSCLC. Strong and independent associations were found between expression of activated AKT (pAKT) and treatment outcome in clinical trials. Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade. To successfully implement these treatments in daily practice, there is a need for molecular predictors of sensitivity to inhibitors of PI3-K/AKT activation. In conclusion, the PI3-K/AKT pathway plays a crucial role in cellular defense mechanisms. Therefore, quantification of the activation status is a potential parameter for predicting treatment outcome. More importantly, specific targeting of this pathway in combination with radiotherapy or chemotherapy may enhance tumor control in NSCLC by antagonizing cellular defense in response to treatment.

Prognostic Significance of Diabetes Mellitus in Locally Advanced Non-small Cell Lung Cancer

“…While pAkt has been studied as prognostic factor in NSCLC, inhibition of pAkt increased apoptosis and improved cellular responsiveness to chemotherapy and irradiation in NSCLC. The combination of EGFR inhibitor and PI3K/ Akt showed additive cytotoxicity [35,36]. Insulin resistance is a characteristic of type 2 DM and leads to hyperinsulinemia.…”

Concomitant EGFR Inhibitors Combined with Radiation for Treatment of Non-small Cell Lung Carcinoma

“…Nonhomologous end-joining is catalyzed by a core complex that consists of a group of proteins, including the DNA dependent protein kinases (DNA/PK), XRCC4, et al The catalytic subunit of DNA-dependent protein kinase (DNA/PKcs) is the key component in the radiation-induced DNA damage repair process, which initiates series of activity that leads to the stabilization of DNA breaks and physical rejoining of DNA DSBs . The EGFR/PI3K/AKT signaling is involved in the intracellular distribution of DNA/PK and activation of the catalytic subunit of DNA/PKcs with the mediation on the transcription of DNA repair genes such as Rad51, ATM, XRCC1, et al, is also the important mechanism by which EGFR and downstream effectors' modification on DNA damage repair (Meyn et al, 2009;Schuurbiers et al, 2009;Debucquoy et al, 2010).…”

Identification of ELAVL4 as a modulator of radiation sensitivity in A549 non-small cell lung cancer cells

“…5A). Because nsclc is known for enhanced pI3K/Akt signaling (15), it is of interest to examine whether endogenous function of ELAVL4 is associated with the signaling for cell proliferation. It is also worth examining whether ELAVL4 activity in RNA processing or translation is responsible for the effect on proliferation.…”

“…the pI3K and Akt signaling pathway has been associated with the radiation resistance phenotype of nsclc (15)(16)(17). In addition genes such as TSPYL5, livin and Mcl-1 were identified as regulators of nsclc in response to DnA damaging agents (18)(19)(20).…”