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American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

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Combined Otolaryngology Spring Meeting
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SIGNIFICANCE OF PIK3CA MUTATIONS IN OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

Presentation: S033
Topic: Basic Science - Molecular Targets/ Exp. Therapeutics
Type: Oral Presentation
Date: Thursday, April 11, 2013
Session: 03:45 PM - 04:45 PM Basic Science
Authors: Andrew B Sewell, MD, Natalia Isaeva, PhD, Wendell G Yarbrough, MD, MMHC, FACS
Institution(s): Yale University, Vanderbilt University

      Despite the shared histology of HPV-positive (HPV+) and HPV-negative (HPV-) oropharyngeal squamous cell carcinoma (OPSCC), HPV(+) tumors have fewer cytogenetic abnormalities and fewer mutations than HPV(-) tumors, confirming different mechanisms driving tumor development and progression. Previously, we found that up to 40% of HPV(+) tumors harbor PIK3CA mutations, which are involved in tumorigenesis and represent an emerging potential target for drug therapy. Many Phase II studies have demonstrated the safety and efficacy of various PI3K/AKT/mTOR inhibitors in patients with breast, lung, and prostate cancer with PIK3CA mutations. However, we have discovered that OPSCC tumors with activating mutations of PIK3CA did not have significantly activated levels of the downstream targets, including AKT and mTOR, most likely due to increased levels of the tumor suppressor PTEN.
      Using a combination of genomic profiling and proteomic studies, we screened 40 prospectively collected OPSCC tumors (23 HPV+, 17 HPV-) for the most common cancer-related PIK3CA mutations. We detected three PIK3CA mutations in eight tumors, with known activating mutations (exon 9, E542K, E545K) seen in 7 tumors; one tumor had a mutation which has been has been shown to be functionally indistinguishable from wild-type PIK3CA. All of the mutant tumors were detected in HPV(+) patients (7/23, 30.4%). Interestingly, in these similarly treated patients, 5-year disease-free survival was 100% in HPV(+) PIK3CA mutant patients, versus 61% in HPV(+) PIK3CA wild-type. These data suggest that PIK3CA mutations may be beneficial and may represent a positive prognostic marker for OPSCC patients receiving traditional chemo- and radio-therapy. Reverse phase protein array (RPPA) probed with 137 antibodies and analyses demonstrated that PIK3CA mutants and wild-type tumors separate into two groups with distinct protein expression profiles, including down-regulated proteins (ERK2, MRE11, mTOR, caspases 3 and 7) and up-regulated proteins (PTEN, p100α, and E-cadherin, among others) in mutant specimens. In contrast, there was no significant difference in phosphorylation of p70S6K, mTOR, and AKT. Immunoblotting for randomly selected tumors, including HPV(+) PIK3CA mutant and wild-type tumors, validated RPPA findings. Activation of downstream targets of PIK3CA signaling can be blocked at several levels, including activation of phosphatases, and/or inhibition of kinase activity. Since we found that the protein levels of the tumor suppressor PTEN were increased in PIK3CA mutant tumors, we suggest that up-regulation of PTEN inhibits PI3K activity by dephosphorylating phosphatidylinositol.
      Although there are many PI3K/AKT/mTOR inhibitors in clinical trials for different types of cancer, it is very important to determine in pre-clinical studies if these inhibitors are effective in PIK3CA-mutant OPSCC tumors. Two available HPV(+) HNSCC cell lines, UM-SCC-47 and UT-SCC-090, harbor wild-type PIK3CA; therefore, E542K and E545K mutations were introduced into wild-type PIK3CA vector using site-directed mutagenesis, and stably overexpressed in HPV(+) cells to perform both short-term cell viability and long-term clonogenic survival assays with the PI3K/AKT/mTOR inhibitors BEZ-235, MK-2206, and GDC-0941. Stable PIK3CA-mutant clones were implanted into NUDE mice to evaluate the in vivo sensitivity of PI3K/AKT/mTOR inhibitors. Future directions and detailed results will be discussed.

 

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