Abstract
The anti-EGFR antibody cetuximab (Erbitux®, CTX) has been introduced into clinical practice for the treatment of SCCHN, as yet with modest effectiveness. Src family targeting agents have shown anti-growth activity in SCCHN preclinical models and are currently considered for further exploration in the same tumor system. In this study we investigated the expression and activation of SRC/STAT pathway components in SCCHN in order to assess how they are related to already in use and upcoming, targeted treatment modalities. Relative expression of SRC, STATs 1,3,5 and related genes was assessed with real time PCR in tumor tissue extracts from SCCHN patients treated with combined radiotherapy and cetuximab-based regimens (RT-CTX). Stat and Akt/PKB protein activation were assessed with immunohistochemistry. SCCHNs always expressed SRC, STAT1, STAT3 and ANXA1 mRNA, variably high levels of IGFBP2 and STAT5A and mostly low STAT5B, PIAS3 and MSN. Stat1, Stat3 and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7% and 70.8%, respectively), although not correlating to the respective STAT mRNA expression levels. Activated Stat3 and Stat5 were associated with each other (p=0.017) and with relatively high CAV1 (pStat3=0.0079; pStat5=0.0107) and MSN (pStat3=0.0463; pStat5=0.0077), as well as with relatively low IGFBP2 expression (pStat3=0.0181; pStat5=0.0328). Akt was phosphorylated at Thr308 in the majority of SCCHN (86.7%) and less so at Ser473 (41.9%) in association with low STAT1 mRNA expression (p=0.0316). All patients with very high expression (upper quartile) of STAT5A and/or EPHA2 experienced a complete response upon RT-CTX treatment (p<0.0001), while all patients without activated Stat1 were also responders (p=0.009). Few tumors (3 of 31, 9.7%) expressed relatively high ANXA1/CAV1/EPHA2 and low IGFBP2, a profile previously proposed to predict response to dasatinib. Very high expression of ANXA1 (an anti-inflammatory molecule possibly associated with chemoradiation resistance) was associated with poor overall (p=0.0009) and progression-free survival (p=0.0004) in this cohort of SCCHN patients. In conclusion, the proposed signature for predicting response to dasatinib in solid tumors is seldom observed in SCCHN. Stat3 and Stat5 activation is common and seems to occur in the anti-oncogenic setting in SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatment. If validated in larger cohorts, these data may be applied for assessing SCCHN patient treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2710.
- ©2010 American Association for Cancer Research
Volume 70, Issue 8 Supplement
