Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Abstract

Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. Conclusions:These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis

“…For negative controls, primary antibody was omitted from the above protocol. The number of positive cells was visually evaluated in each core by a pathologist (Dr. S-Y X) and the staining intensity of Akt1, Akt2 or PTEN classified using a five-grade scale, with 0 indicating the absence of immunostaining or less than 10% of stained cells; 1, between 10% and 25%; 2, between 25% and 50%; 3, 50% to 75%; and 4, 75% to 100% of cells stained (22).…”

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…Indeed, aberrant activation of mTOR has been shown in several cancers, including kidney, breast, and the head and neck carcinomas. 8,16,17 Thus, mTOR is considered an attractive target of anticancer agents. One agent, the bacterial macrolide rapamycin, which inhibits mTOR activity, has emerged as a validated novel anticancer therapeutic.…”

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

“…The PI3K‐AKT‐mTOR signaling pathway is a vital pathway for growth, survival, and metabolism for which there is evidence of frequent functional signal activation in HNSCC cell lines and tumors 25, 26, 27, 28, 29. Genetic aberrations such as CNAs, mutations, and dysregulation of mRNA are prevalent.…”