Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival

University of South Florida, Tampa, Florida, United States
Cancer Research (Impact Factor: 9.28). 07/2006; 66(11):5542-8. DOI: 10.1158/0008-5472.CAN-05-4620
Source: PubMed

ABSTRACT Mutations of the epidermal growth factor receptor (EGFR) selectively activate Akt and signal transducer and activator of transcription (STAT) pathways that are important in lung cancer cell survival. Src family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules, such as phosphatidylinositol 3-kinase/PTEN/Akt and STATs. Based on the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and Src proteins, and evidence of elevated Src activity in human lung cancers, we evaluated the effectiveness of a novel orally bioavailable Src inhibitor dasatinib (BMS-324825) in lung cancer cell lines with defined EGFR status. Here, we show that cell fate (death versus growth arrest) in lung cancer cells exposed to dasatinib is dependent on EGFR status. In cells with EGFR mutation that are dependent on EGFR for survival, dasatinib reduces cell viability through the induction of apoptosis while having minimal apoptotic effect on cell lines with wild-type (WT) EGFR. The induction of apoptosis in these EGFR-mutant cell lines corresponds to down-regulation of activated Akt and STAT3 survival proteins. In cell lines with WT or resistant EGFR mutation that are not sensitive to EGFR inhibition, dasatinib induces a G(1) cell cycle arrest with associated changes in cyclin D and p27 proteins, inhibits activated FAK, and prevents tumor cell invasion. Our results show that dasatinib could be effective therapy for patients with lung cancers through disruption of cell growth, survival, and tumor invasion. Our results suggest EGFR status is important in deciding cell fate in response to dasatinib.

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    • "Shown are representative blots of three independent experiments. cancer cells posses other active pro-survival signaling pathways such as EGFR, STAT3 and c-Met [17] [30] [42] [44] [45]. "
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    • "In the absence of any known naturally occurring activating mutations in the STAT3 gene, aberrant STAT3 activation is predominantly due either to persistent Y phosphorylation signals emanating from dysregulated upstream tyrosine kinases, such as hyperactive growth factor receptors or non-receptor tyrosine kinases, including Src or JAKs, or to the over-expression of stimulatory ligands, such as EGF or IL- 6 [17]. These molecular events are exemplified by the constitutive activation of STAT3 mediated by the persistent stimulation of the IL-6/gp130 and the JAK/STAT pathways in multiple myeloma (MM), large granular lymphocyte (LGL) leukemia, and prostate cancer [18] [19] [20], as well as by elevated EGFR-mediated signaling and the activity of Src and JAKs in breast cancer, prostate cancer, non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, and head and neck squamous carcinoma (HNSCC) cells [21] [22] [23] [24] [25] [26] [27] [28] [29]. "
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