Abstract 3340: Exploiting the non-overlapping dysregulation of Notch and PI3K/AKT signaling pathways as a guide for personalizing uterine cancer therapy
Authors: Previs Rebecca A. , Ivan Cristina , Dalton Heather J. , Davis Ashley N. , Bottsford-Miller Justin N. , Zand Behrouz , McGuire Michael H. , Armaiz-Pena Guillermo N. , Coleman Robert L. , Baggerly Keith A. , Sood Anil K. 
Published: May 2015

Objective: The Notch pathway plays a critical role in cell-to-cell communication, proliferative signaling, and cell differentiation, but can have oncogenic or tumor suppressive effects depending on the tissue type. Dysregulation of the PI3K/AKT pathway has been implicated in a variety of cancers and represents an attractive therapeutic target. We analyzed the clinical significance and interplay of these two pathways in endometrial cancer.

Methods: We accessed clinical, somatic mutations, and Reverse Phase Protein Array (RPPA) data from The Cancer Genome Atlas (TCGA) to perform integrated analyses and determine the clinical significance of Notch pathway aberrations in uterine cancer patients. In this cohort, we also identified concomitant PI3K/AKT abnormalities. Clinical information extracted included age, BMI, tumor histology, tumor grade, clinical stage, estrogen(ER)/progesterone(PR) receptor status, and overall survival.

Results: A total of 232 samples were available for analysis. Within the Notch pathway, 18.1% of evaluable samples had amplification or upregulation of Notch2/Notch3 and/or DLL3 genes, which was significantly correlated with worse overall survival (p=3.08e-7). Median ERα, ERα(pS118), and PR RPPA levels were significantly higher for patients with no abnormalities or mutations present in Notch2/Notch 3 and/or DLL3 than those with amplification and/or upregulation of these genes (p=0.0016, p=0.0002, and p=0.003, respectively). Of the 52 identified mutations in Notch2/Notch3 and/or DLL3, 92.3% and 7.7% were missense and nonsense mutations, respectively. PI3KCA represented the most frequently mutated gene within this subset affecting 59% of patients; 159 mutations were identified and 95% were missense mutations. Overexpression or amplification of mRNA involved in the PI3K/AKT pathway was present in 108 (46.5%) of the evaluated endometrial tumors. Of these, only 35 tumors (32.4%) had overlapping, concomitant Notch2/Notch3/DLL3 mRNA overexpression or amplification.

Conclusions: Upregulation or amplification of Notch 2, Notch 3, and/or DLL3 genes predicted a more aggressive clinical course for endometrial cancer patients. Given the non-overlapping expression of PI3K/AKT and Notch pathways, personalized options for targeted therapy could be considered for each group.

Citation Format: Rebecca A. Previs, Cristina Ivan, Heather J. Dalton, Ashley N. Davis, Justin N. Bottsford-Miller, Behrouz Zand, Michael H. McGuire, Guillermo N. Armaiz-Pena, Robert L. Coleman, Keith A. Baggerly, Anil K. Sood. Exploiting the non-overlapping dysregulation of Notch and PI3K/AKT signaling pathways as a guide for personalizing uterine cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3340. doi:10.1158/1538-7445.AM2014-3340