Abstract 2388: Genetic determinants of sensitivity and resistance to PI3K inhibitors in head and neck cancers for efficient targeted therapy.
Authors: Mazumdar Tuhina , Byers Lauren A. , Peng Shaohua , Diao Lixia , Hale Katherine S. , Glisson Bonnie S. , Johnson Faye M. 
Published: August 2014

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with 600,000 new cases and 350,000 cancer deaths each year worldwide. It is a disabling and disfiguring cancer with a profound impact eating, speaking, and appearance. We need better systemic treatment for HNSCC. Targeted therapy can be remarkably effective if it inhibits key oncogenic drivers but no such targets have yet been identified in HNSCC. To identify potential targets, we screened sixty validated HNSCC cell lines using Sequenom for a panel of sixty potentially targetable mutations commonly found in squamous cancers. In addition, we used SNP CHIP to identify gene copy number gain or loss. Alterations in the PI3K pathway were the most commonly identified molecular targets in HNSCC cell lines. Likewise, the PI3K signaling pathway is commonly altered in multiple cancers driving cancer cell growth and survival. We identified 5 cell lines with PIK3CA mutations, 5 cell lines with PIK3CA amplification, and 2 cell lines with PTEN loss. We tested these cell lines along with those lacking identified PI3K pathway alterations for sensitivity to two PI3K inhibitors (GDC0941, GSK1059615), one dual PI3K/mTOR inhibitor (GDC0980), one AKT inhibitor (GSK690693) and one mTOR inhibitor (AZD8055). The 5 cell lines with PIK3CA mutations were almost universally sensitive to all inhibitors whereas those with PI3KCA gene amplification were almost universally resistant to all inhibitors. Among two cell lines with PTEN loss, one was sensitive and other resistant to the inhibitors. Cell lines lacking identified PI3K pathway alterations had mixed sensitivity. We measured basal activation of several pathway components including pAKT, pS6, p4EBP1 and found that only pS6 predicted response to PI3K pathway inhibitors. Following treatment with PI3K inhibitors, we discovered an increase in pERK and insufficient inhibition of cMYC in resistant cell lines, but not in sensitive cell lines. The combination of PI3K and MEK inhibition was synergistic in resistant cell lines. Our study identified that among the different types genetic lesions in the PI3K pathway, PIK3CA mutations are the best predictors of sensitivity to pathway inhibitors. In resistant HNSCC combinations with MEK inhibitors may be effective. Multiple inhibitors of the PI3K and MEK/ERK pathways are in clinical development making the clinical application of our data possible in the near future.

This work was supported by University of Texas SPORE in Head and Neck Cancer P50 CA097007.

Citation Format: Tuhina Mazumdar, Lauren A. Byers, Shaohua Peng, Lixia Diao, Katherine S. Hale, Bonnie S. Glisson, Faye M. Johnson. Genetic determinants of sensitivity and resistance to PI3K inhibitors in head and neck cancers for efficient targeted therapy. [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 2388. doi:10.1158/1538-7445.AM2013-2388