Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

Abstract

The traditional classification of lung cancer into small cell lung cancer and non‐small cell lung cancer (NSCLC) has been transformed with the increased understanding of the molecular alterations and genomic biomarkers that drive the development of lung cancer. Increased activation of the phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway leads to numerous hallmarks of cancer and this pathway represents an attractive target for novel anticancer therapies. In NSCLC, the PI3K/Akt/mTOR pathway has been heavily implicated in both tumorigenesis and the progression of disease. A number of specific inhibitors of PI3K, Akt and mTOR are currently under development and in various stages of preclinical investigation and in early phase clinical trials for NSCLC. Early evidence has yielded disappointing results. Clinical trials, however, have been performed on predominantly molecularly unselected populations, and patient enrichment strategies using high‐precision predictive biomarkers in future trials will increase the likelihood of success. A greater understanding of the underlying molecular biology including epigenetic alterations is also crucial to allow for the detection of appropriate biomarkers and guide combination approaches.

<p>Knockdown of circPRKCA Restrained Cell Growth, Migration, and Invasion of NSCLC Cells Both in vitro and in vivo via Regulating miR-330-5p/PDK1/AKT Pathway</p>

“…A great deal of evidence had revealed that the AKT signal was heavily implicated in the tumorigenesis, progression, and therapy of cancers including NSCLC. 5,24 Thus, expression of p-AKT was measured, and Western blotting manifested that relative p-AKT expression was suppressed by si-circPRKCA#3 transfection in A549 and H1299 cells ( Figure 2H). These outcomes indicated a suppressive role of circPRKCA knockdown in NSCLC cell growth, migration, invasion, and AKT activity in vitro.…”

“…4 Furthermore, phosphoinositide 3-kinase (PI3K)/AKT signaling, a key prosurvival pathway in cancer cells, has been proposed as an attractive target for novel anticancer therapies in NSCLC. [5][6][7] Therefore, identifying novel biomarkers that target the PI3K/AKT pathway is of great importance to better understand the malignant development of NSCLC.…”

UBR-Box containing protein, UBR5, is over-expressed in human lung adenocarcinoma and is a potential therapeutic target

“…Proteins in this pathway are often reported to be mutated or ampli ed in lung adenocarcinomas. Also, the mTOR complex is known to activate AKT through phosphorylation at Serine 473 [34,35]. Our IP data suggests a direct interaction of UBR5 with proteins of the mTOR complex, including Raptor and Rictor.…”

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70

“… 37 – 39 In this study, activation of AKT by phosphorylation was further confirmed when HSP70 was increased, which may further activate mTOR via TSC2 phosphorylation that subsequently stimulates Rheb, which then activates the multiprotein complex mTORC1 and mTORC2. 40 In addition, mTOR inhibitors instead of HSP70 inhibitors were chosen to interfere with this signaling, as mTOR inhibitors could not only suppress the HSP70 induced signaling, but also several other pro-oncogenic pathways. This way, we may allow the use of minimum drug concentrations, but achieve a maximum effect.…”