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. Author manuscript; available in PMC: 2017 Jul 1.
Published in final edited form as: Mol Cancer Ther. 2016 May 11;15(7):1669–1681. doi: 10.1158/1535-7163.MCT-15-0182

Figure 6. Significant percentage of human lung cancer tumors are WEE1 and PAXIP1 positive and double positive patient-derived xenografts exhibit synergy with AZD1775 and cisplatin.

Figure 6

(A) Representative lung adenocarcinoma tumors with immunohistochemistry staining for WEE1, PAXIP1 and hematoxylin & eosin. (B) Tissue microarrays (TMAs) were evaluated for tumors that are PAXIP1 and WEE1 positive. In TMA1 with 95 tumors of multiple lung histologies, 35% tumors were WEE1 and PAXIP1 positive as shown in the red band of the circos plot. In an adenocarcinoma-only TMA with 138 tumors, TMA2, 27% of the tumors are positive for WEE1 and PAXIP1. In a TMA with 80 squamous cell carcinoma-only tumors, TMA3, 19% were positive for WEE1 and PAXIP1. (C) Two tumors that were selected from a TMA of 68 lung tumors for 3-D clonogenic assays to test synergy of the combination of AZD1775 and cisplatin in these tumors. (Left Panel) Percentage of tumor inhibition with different concentrations of AZD1775 and cisplatin are indicated here. (Right Panel) Combination index (CI) values were obtained by applying the Chou-Talalay analysis to the percent inhibition values. pCI[–log(CI)] values were plotted to assess synergy. Values indicated in red exhibit synergy at physiologically relevant drug concentrations (D) Schematic to represent the role of PAXIP1 in the regulation of the phosphorylation of CDK1 by WEE1. PAXIP1 overexpression along with AZD1775 treatment (with cisplatin or IR) in cells causes them to progress through mitosis and undergo apoptosis. Therefore, cells expressing both WEE1 and PAXIP1 have higher levels of apoptosis compared to those that do not express PAXIP1 and/or WEE1.