Abstract 2011: The PI3K pathway is the most frequently mutated mitogenic pathway in HNSCC.
Authors: Hedberg Matthew L. , Lui Vivian , Li Hua , Vangara Bhavana , Pendleton Kelsey , Zeng Yan , Gilbert Breean , Freilino Maria , Sauerwein Sam , Peyser Noah , Diergaarde Brenda , Hammerman Peter , Garraway Levi , Mills Gordon , Grandis Jennifer 
Published: August 2014

The genomic heterogeneity of HNSCC presents a major obstacle to broadly effective targeted therapy. We and others previously reported genomic mutational profiles of over 100 HNSCC tumors. To date, there has been a major translational gap between genomic findings and patient treatment selection in HNSCC. Mitogenic pathways are vital to cancer development and progression. Genetic mutations in mitogenic pathways have been shown to result in pathway activation, increased proliferation of tumor cells, and increased sensitivity to agents targeting the specific pathway. Here, we performed a bioinformatics analysis of 151 HNSCC to examine the mutational profiles of major mitogenic pathways previously shown to be important in HNSCC tumor biology, including MAPK, JAK/STAT and PI3K, and found that the PI3K pathway is the most frequently mutated mitogenic pathway (30.46% cases; 46/151 tumors) followed by JAK/STAT and MAPK, (9.27% cases; 14/151 tumors) and (7.95% cases; 12/151 tumors), respectively.

HNSCC tumors with mutations in PI3K harbored 2.3 times more non-synonymous mutations (165.50 ± 24.08 vs 72.05 ± 6.63 mutations, P&lt;0.0001) and twice as many cancer gene mutations than the HNSCC tumors without any PI3K pathway mutations (7.15 ± 0.75 vs 3.56 ± 0.29 mutations, P&lt;0.0001), including multiple mutational events of genes in the PI3K pathway, suggesting that PI3K pathway mutations may promote the expansion of HNSCC tumor cells that are already genetically unstable. Interestingly however, in a small subset of HPV-positive HNSCC tumors (3 out of 45), PIK3CA was the only cancer gene found to be mutated, suggesting that the PI3K pathway alone may be sufficient to drive some HPV-positive HNSCC. The observed frequency of PIK3CA mutation in our 151 HNSCC cohort (12.58%; 19 mutations total) is higher than that reported previously in other smoking-related cancers such as lung cancer and esophageal cancer, where the respective PIK3CA mutation rates are not greater than 3-5%, suggesting a likely enrichment of PIK3CA mutations in HNSCC. Other components of the PI3K pathway were mutated in &lt;2 - 3.97% of HNSCC tumors sequenced. Major downstream effectors of the PI3K pathway, including PDK1, AKT1 were not mutated, while AKT2 and mTOR were mutated in just 1.29% (2 mutations) of HNSCC tumors.

Importantly, PIK3CA and the PI3K pathway are currently targetable in human cancers, with several agents in various stages of clinical development. The growth of HNSCC xenografts derived from a cell line with a PIK3CA(H1047R) mutation, treated with the mTOR/PI3K inhibitor BEZ-235, was significantly inhibited. These findings suggest that PIK3CA, and potentially other PI3K pathway, mutations may serve as predictive biomarkers in HNSCC to guide treatment selection.

Citation Format: Matthew L. Hedberg, Vivian Lui, Hua Li, Bhavana Vangara, Kelsey Pendleton, Yan Zeng, Breean Gilbert, Maria Freilino, Sam Sauerwein, Noah Peyser, Brenda Diergaarde, Peter Hammerman, Levi Garraway, Gordon Mills, Jennifer Grandis. The PI3K pathway is the most frequently mutated mitogenic pathway in HNSCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2011. doi:10.1158/1538-7445.AM2013-2011