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Exploration of Cancer Proliferative Signaling in Chemotherapy Drug Resistance and Mdig-induced Tumorigenesis

Kai Wu

出版	Wayne State University, 2016
URL	http://books.google.com.hk/books?id=IivcuQEACAAJ&hl=&source=gbs_api

註釋

Using integrative genomics and proteomics approaches, we further demonstrated that in MM cell lines, mdig directly interacts with c-myc and JAK1, which contributes to hyperactivation of the JAK-STAT3 signaling important for the pathogenesis of MM. Genetic silencing of mdig reduced activity of the major downstream effectors in the JAK-STAT3 pathway. Our results indicate that WTC dust induced-mdig overexpression bridges c-myc pathway and STAT3 pathway in MM, which is essential for the tumorigenesis of MM. In the second project, we focused on the underlying mechanisms of both primary and secondary resistance to EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor), including gefitinib, in NSCLC (Non-small cell lung cancer), which are two major obstacles compromising the clinical success of targeted therapy. In the part studying primary resistance, we observed that JAK2-STAT3 signaling axis in non-sensitive lung cancer cell lines is highly refractory to gefitinib treatment. Follow-up experiments further revealed a unique STAT3-dependent Akt restoration pattern in non-sensitive lung cancer cells, which impairs the efficacy of gefitinib. Mechanistically, gefitinib increased physical binding between EGFR and STAT3, which de-repressed STAT3 from SOCS3, an upstream suppressor of STAT3. Such a de-repression of STAT3 in turn fostered Akt activation. Genetic or pharmacological inhibition of STAT3 abrogated Akt activation and combined gefitinib with STAT3 inhibition synergistically reduced the growth of the tumor cells. In order to study the mechanisms of secondary resistance (acquired resistance), we established a gefitinib-resistant lung cancer (GR) cell line. Through profiling the gene expression pattern and investigating the alterations of intracellular signaling pathways, we discovered multiple resistance mechanisms in GR cells, including a unique hyperactivation pattern of STAT3. A rational co-inhibition of STAT3 and EGFR simultaneously suppressed several survival-related pathways in GR cells. As a result, such combinational targeting re-sensitized the GR cells to gefitinib treatment. Taken together, our study has unraveled novel mechanisms of resistance to EGFR TKI in lung cancer and has provided important information for rationale-based combinational targeting strategies to overcome drug resistance.