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“Introduction Non-small-cell lung cancer (NSCLC) has become the leading cause of cancer-related death in Western countries where the majority of patients present with advanced or metastatic disease
[1]. The overall poor prognosis and the plateau of improvement in response and survival outcomes seen with chemotherapy over the last two decades, highlight the need for additional therapeutic strategies [2]. Over the last few years epidermal growth factor receptor (EGFR) has been identified as a promising therapeutic Selleck TSA HDAC target due to its correlation with adverse disease characteristics such as advanced stage at diagnosis, and resistance to treatment [3–5]. Erlotinib (Tarceva®, OSI-Pharmaceuticals,
New York, NY) was approved as mono-therapy in the second-third-line treatment of lung cancer [6]. This tyrosine kinase Selleckchem PXD101 inhibitor (TKI) along with gefitinib (Iressa®, AstraZeneca, Macclesfield, UK) reversibly bind the ATP-binding pocket of the EGFR tyrosine kinase domain, thereby inhibiting auto-phosphorylation and stimulation of downstream signaling pathways resulting in inhibition of proliferation, delayed cell cycle progression, and increased apoptosis [7–11]. The more recent understanding that both of these agents display extremely high response rates in patients harboring somatic mutations in EGFR has resulted in the first SHP099 solubility dmso molecularly stratified licensing approval for a drug in NSCLC [12]. Subsequent to the recent publication of the IPASS study, gefitinib
was awarded license for the treatment of first line, chemotherapy naive advanced or metastatic patients with NSCLC based upon molecular stratification for the presence of activating somatic EGFR mutations [13]. Somatic mutations in the EGFR tyrosine kinase domain are correlated Histamine H2 receptor with improved response rates with both of these agents [14]. However, this is not the only biomarker correlated with response, EGFR gene gain is also a well characterised biomarker of TKI response [15], and there is evidence of co-segregation of mutation and gene gain [1, 16]. Other predictive biomarkers have also been identified including a biomarker of non-responsiveness, somatic mutations in KRAS; these are also known to be mutually exclusive from EGFR[17]. Moreover, there are a number of patients who either do not respond in the presence of known predictive biomarkers, or who develop resistance to anti-EGFR TKIs. Several of the candidate biomarkers of either ‘acquired’ or ‘de-novo’ resistance to TKI treatment include secondary EGFR mutations (including T790M), and cMET gene gain [18]. In this retrospective clinical – translational study we aimed to characterise several of these molecular events and correlate them with response and outcome of patients treated with either of the EGFR TKIs.