Anti-PIK3R1 monoclonal antibody, clone 4D22

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. (C) 2013 AACR.

This review examines the main toxic effects of phosphatidylinositol 3-kinase inhibitors and recommends approaches to identification and management of such toxic effects. ImportanceThe phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, which regulates multiple cellular processes, including metabolism, proliferation, motility, growth, and survival, is one of the most frequently dysregulated pathways in human cancers. The PI3K/AKT/mTOR cascade can be aberrantly activated by multiple factors, including diverse oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, MTOR, and other critical genes, which can be used as targets for anticancer therapy. Limited single-agent activity, high levels of toxic effects, and a lack of predictive biomarkers for treatment selection have all been major barriers to the clinical development of these compounds. Many adverse effects are uncommon and have poorly understood mechanisms. An understanding of these toxic effects, as well as a better definition of management guidelines, will be important because more PI3K inhibitors are under development and may soon be incorporated into routine practice. ObservationsA search of PubMed, draft prescribing information of currently approved PI3K inhibitors, European Medical Association and US Food and Drug Administration product information, and expert panel opinion on the management of the prominent toxic effects of this class of agents was conducted on August 29, 2018. This article provides an overview of the main toxic effects of PI3K inhibitors reported in clinical trials and a summary of recommendations for identification and management of treatment-emergent toxic effects, including hypoglycemia, cutaneous reactions, pneumonitis, neuropsychiatric effects, hepatotoxic effects, diarrhea, and colitis. Overall, the clinical development of most PI3K inhibitors has been discontinued owing to insufficient activity, problematic toxic effects, and the absence of biomarkers correlated with clinical activity. Knowledge of the isoforms and their distribution in tissue can help clinicians anticipate toxic effects. Notably, novel, more specific inhibitors for individual isoforms of PI3K showed therapeutic activity with improved toxic effect profiles compared with non-isoform-selective agents. Conclusions and RelevanceAn improved understanding of the complexities of the main toxic-effect mechanisms and their management might open viable paths to advancing PI3K inhibitors from clinical studies to new standard-of-care treatments.