Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway–mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA–wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection. Significance: Treatment options for HNSCC are limited, in part, because of an incomplete understanding of the targetable mutations that “drive” tumor growth. Here, we define a subgroup of HNSCC harboring activating mutations of genes in the PI3K pathway where targeting the pathway shows antitumor efficacy. These results suggest that PI3K pathway mutation assessment may be used to guide HNSCC therapy. Cancer Discov; 3(7); 761–9. ©2013 AACR. See related commentary by Iglesias-Bartolome et al., p. 722 This article is highlighted in the In This Issue feature, p. 705

Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal–regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN. Cancer Res; 72(13); 3270–81. ©2012 AACR.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

The signal transducer and activator of transcription (STAT) proteins relay signals from cytokine receptors and receptor tyrosine kinases on the cell surface to the nucleus, where they affect the transcription of genes involved in normal cell functions, including growth, apoptosis and differentiation. STAT3 has been found to be constitutively active in head and neck squamous cell carcinoma (HNSCC) as well as in other epithelial malignancies. In HNSCC, STAT3 alters the cell cycle, prevents apoptosis, and mediates the proliferation and survival of tumour cells. Several therapeutic approaches are being developed to target STAT3, including molecules that block either dimerisation or DNA binding by STAT3, strategies to decrease STAT3 expression and drugs that inhibit STAT3 function. Strategies that block STAT3 may prove efficacious for cancer treatment.

Despite recent advances in the understanding of the biologic basis of hepatocellular carcinoma (HCC) development, the clinical management of the disease remains a major challenge. Deregulation of the PI3K/Akt/mTOR pathway, which is a prototypic survival pathway, is increasingly implicated in HCC carcinogenesis. In this article, we detailed the role of this pathway in the pathogenesis of HCC and provide an update on the preclinical and clinical development of various agents targeting this key survival/proliferation pathway, which include various PI3K inhibitors, Akt inhibitors and mTOR inhibitors for HCC. In addition, we highlighted the therapeutic potential of combination strategy for mTOR inhibitors with conventional chemotherapy, in particular, antimicrotubule agents, other molecular targeting agents, as well as radiotherapy.