LAUSR

We previously showed the MAPK pathway can be mutationally activated, and may implicate drug sensitivity in HNSCC [1]. Here, we report that RNA expression of several MAPK pathway components may be associated with HNSCC patients9 outcome based on the US-TCGA Provisional data. We found that loss of DUSP4, a negative regulator of MAPK pathway, was correlated with poor overall survival (OS; P=0.0286) and disease free survival (DFS) in HNSCC (0.00150; median progression time = 38.11 vs. 71.22 months in DUSP4-unaltered patients) which can potentially be explained by activation of oncogenic MAPK pathway upon DUSP4 underexpression. Interestingly, we identified a group of HNSCC patients with homozygous loss and mRNA downregulation of MAPK pathway scaffold protein components (GRB2, SHC2 and SHC3) with significantly poorer DFS (P=0.000871). RPPA analysis showed a trend of decreased protein expression level of phospho-RAFs, downstream of scaffold proteins, decreased MEKs and MAPKs, supportive of an overall decreased MAPK pathway signaling in this subset of patients. Unexpectedly, downregulation (homozygous deletion/ RNA expression less than 2 SD) of multiple MAPK pathway components which normally support activation of the pathway: RAF1 (9%), MAPK1 (3%) and RPS6KA1 (1.9%) was found to be significantly associated with poorer DFS (P=6.643x10^-5) with median time to progression of 18.17 months vs. 71.22 months in the unaltered group. Subsequent proteomic analysis of the respective patient tumors from the TCGA cohort (N=357 with RPPA data) showed that these patient tumors had elevated levels of E2F1 protein expression (P=0.0146), along with increase FOXM1 expression (P=8.499x10^-4), which is known to drive cell cycle progression [2]. As E2F1 is involved in cell survival upon DNA damage [3], it is likely that upregulation of E2F1 protein expression may enable cancer cells to survive after DNA insults by radiotherapy or chemotherapy, and contributes to disease relapse. Acknowledgements: VWYL is funded by the Research Grant Council, Hong Kong (#17114814, General Research Fund), Theme-based Research Scheme (T12-401/13-R), and the Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong. Reference: 1. Van Allen, E.M., et al., Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma. JAMA Oncol, 2015. 1(2): p. 238-44. 2. Barger, C.J., et al., Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression. Oncotarget, 2015. 6(29): p. 27613-27. 3. Berton, T.R., et al., Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation. Oncogene, 2005. 24(15): p. 2449-60. Citation Format: Hoi Lam Ngan, Vivian W.Y. Lui. Potential clinical significance of downregulation of MAPK pathway components mRNA expression in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5712. doi:10.1158/1538-7445.AM2017-5712