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• W2035682058 abstract "Background: Targeted therapy for head and neck squamous cell carcinoma (HNSCC) is currently limited to EGFR inhibition with agents such as cetuximab. We and others have previously demonstrated that epithelial to mesenchymal transition (EMT) is associated with resistance to EGFR inhibitors in HNSCC and lung cancers but greater sensitivity to other targeted drugs, such as AXL inhibitors. Here, we apply a previously published EMT signature to identify novel potential therapeutic targets (PTTs) in mesenchymal HNSCC tumors (MHNTs).Methods: A high-throughput analysis of gene and protein expression in HNSCC tumors from The Cancer Genome Atlas (TCGA) (A, n=113) was performed to identify PTTs in MHNTs. Specifically, the EMT signature score for each tumor was correlated with marker expression levels by Pearson correlation (mRNA, protein) or t-test (mutation, HPV status). PTTs were validated in an independent cohort of high-risk, resected tumors (B, n=105) and HNSCC cell lines (C, n=60). PTTs were defined as druggable targets found on recent HNSCC publications, our in-house targeted sequencing panel of 202 genes and publicly available cancer cell lines drug sensitivity datasets (DSDs).Results: At a false discovery rate of 1% (p 0.5) and confirmed in our independent cohort included DDR2, FGFR1, KDR, MMP14, MMP2, PDGFRA, PDGFRB and TGFBR2. Targets that were overexpressed in both tumors and cell lines included NOTCH4 (A and B p<0.001; C p<0.04), which is known to play a role in EMT, and ABL1 (A and B, p<0.001; C p<0.01). Protein expression data was available for three out of the 36 validated PTTs and confirmed the mRNA findings, with higher protein levels observed for Axl, cKit and PKC-alpha in mesenchymal tumors (cohort A). Using publicly available in vitro DSDs, we then explored whether increased expression of PTTs was associated with greater sensitivity to specific targeted agents. We found increased sensitivity of mesenchymal cell lines, compared with epithelial ones, to FGFR1, PDGFRA and KDR inhibitors, such as ponatinib and pazopanib. Finally, mutational and HPV analysis of the TCGA cohort showed that mesenchymal tumors had higher rates of TP53 (p=0.044) and RSAP58 (p=0.029) mutations and infrequent PIK3CA or NSD1 mutations (p<0.001 for both). They were predominantly HPV-negative (p=0.024).Conclusions: An integrated analysis of EMT and expression data from two independent cohorts identifies previously unrecognized, candidate PTTs in mesenchymal HNSCC tumors. Validation of the PTTs at the protein level is ongoing. The approach described may identify patient subsets, beyond mutational status, for whom targeted therapy can be successful.Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A131.Citation Format: Milena P. Mak, Lixia Diao, Jing Wang, Patrick KS Ng, You-Hong Fan, Michael D. Story, William N. William, John V. Heymach, John N. Weinstein, Kevin R. Coombes, Lauren A. Byers. Identification of candidate therapeutic targets in mesenchymal head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A131." @default.
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• W2035682058 date "2013-11-01" @default.
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• W2035682058 title "Abstract A131: Identification of candidate therapeutic targets in mesenchymal head and neck squamous cell carcinoma." @default.
• W2035682058 doi "https://doi.org/10.1158/1535-7163.targ-13-a131" @default.
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