Abstract
IntroductionTargeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20–30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study.MethodsTargeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC.ResultsFour patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research.ConclusionMDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.
Highlights
Targeted therapy for Non-small-cell lung cancer (NSCLC) is rapidly evolving
murine double minute 2 (MDM2) amplification predicted a poor prognosis in NSCLC patients and was associated with a short progression-free survival (PFS) in those treated with epidermal growth factor receptor (EGFR)-TKIs
In addition to acquired resistance, multiple genomic alterations have been proven to be associated with primary resistance to EGFR-TKIs, such as the pre-existing T790M mutation (Inukai et al 2006; Lee et al 2014), insulin-like growth factor 1 receptor (IGF1R) mutation (Sharma et al 2010), MET amplification (Turke et al 2010), hepatocyte growth factor (HGF) mutation (Yano et al 2008) and mutations leading to sustained activated signaling in other pathways, including the PI3K/AKT pathway (Tan et al 2015)
Summary
Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. 20–30% of patients demonstrate primary resistance to EGFRTKIs, which leads to the failure of EGFR-TKI treatment. Patients may develop resistance to first generation EGFR-TKIs, which leads to treatment failure. In addition to acquired resistance, multiple genomic alterations have been proven to be associated with primary resistance to EGFR-TKIs, such as the pre-existing T790M mutation (Inukai et al 2006; Lee et al 2014), insulin-like growth factor 1 receptor (IGF1R) mutation (Sharma et al 2010), MET amplification (Turke et al 2010), hepatocyte growth factor (HGF) mutation (Yano et al 2008) and mutations leading to sustained activated signaling in other pathways, including the PI3K/AKT pathway (Tan et al 2015). We performed this study to confirm our hypothesis that MDM2 amplification contributes to the primary resistance to first-generation EGFR-TKIs in NSCLC
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