Whole-Exome Sequencing Of Gastric Cancer Identifies Germline Pik3r1 Variant As A Novel Genetic Biomarker For A Pi3k Beta-Isoform Selective Inhibitor, Gsk2636771

BACKGROUND: PI3K signaling is one of the most frequently altered pathways in gastric cancer (GC), and PI3K beta-isoform selective inhibitors have anti-tumor effects with tolerable toxicities in PTEN loss driven tumors. This study aimed to identify novel genetic predictive factors for a PI3K beta-isoform selective inhibitor through a whole-exome analysis of GC cell lines. METHODS: We comprehensively analyzed the genetic alterations in 40 GC cell lines using whole-exome sequencing (WES) and identified specific genetic alterations with sensitivity to GSK2636771, a PI3K beta-isoform selective inhibitor. RESULTS: We identified frequent genetic alterations in PI3K family genes (PIK3CA: 20%, PIK3C2B: 15%, PIK3CD 13%, PIK3CG: 25%, PIK3R1: 30%, PIK3R2: 100%). While no deletion or mutation of PTEN was detected, 40% exhibited a loss of PTEN protein expression. Intriguingly, we noticed germline PIK3R1 variant, M326I (rs3730089), was significantly related to the increased sensitivity to GSK2636771 (IC50: 20.6±9.0 vs 43.5±26.8 μM, p = 0.001), with a stronger association than that of PTEN loss (IC50: 27.5±13.9 vs. 41.7±28.0 μM, p = 0.047). GC cell lines with higher variant allele frequency of PIK3R1 tended to be more sensitive to GSK2636771. Moreover, PIK3R1 M326I was associated with increased p85α expression (p = 0.0198) and decreased PTEN expression in GC cell lines (p = 0.008); same findings were also confirmed in human GC tissues. Furthermore, a correlation analysis of PIK3R1 and PTEN expressions in GC tissues revealed the reciprocal association between these two proteins (R2 = 0.223, p = 0.002), suggesting the possible mechanistic role of PIK3R1 as a negative regulator of PTEN, or vice versa in GC. Next, among various cytotoxics, oxaliplatin was significantly more effective in PIK3R1 M326I variant GC cells (p = 0.028), supporting the combination of GSK2636771 and oxaliplatin for further clinical development in GC. Finally, by using both the PIK3R1 M326I and PTEN loss in combination, we were able to predict the response to GSK2636771 more accurately in GC cells. CONCLUSION: Through WES analysis of GC cell panels, we identified a germline PIK3R1 variant, M326I, as a novel genetic biomarker that provides a more accurate prediction of response to GSK2636771 when used in combination with PTEN loss. Citation Format: Chan Kim, Woo Sun Kwon, Sun Young Rha, Sun Kyung Kang, Hyoki Kim, Carolyn Buser-Doepner, Li Yan, Rakesh Kumar, Hyun Cheol Chung. Whole-exome sequencing of gastric cancer identifies germline PIK3R1 variant as a novel genetic biomarker for a PI3K beta-isoform selective inhibitor, GSK2636771. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4694. doi:10.1158/1538-7445.AM2015-4694