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R. Sakai

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-003 - The PDGFR/Src signaling pathway-targeted therapy with novel TUSC2-nanoparticles and tyrosine kinase inhibitors for human lung cancer (ID 1194)

      09:30 - 16:30  |  Author(s): R. Sakai

      • Abstract

      The PDGFR is among the significantly mutated pathways and the PDGFR and downstream Src family protein kinases are often aberrantly activated and play important roles in mediating oncogenic signaling and modulating sensitivity to the molecularly-targeted therapy in lung cancer. We have previously shown that the novel tumor suppressor TUSC2 (FUS1) functions as a key mediator in the apoptosis signaling pathway and down-regulates activities of multiple oncogenic protein kinases such as EGFR, PDGFR, Src, and c-Abl in lung cancer cells. A systemic treatment with FUS1-DOTAP:Cholesterol nanoparticles demonstrated a potent antitumor efficacy in preclinical lung cancer animal models and showed promising clinical benefits in advanced lung cancer patients.

      In this study, we evaluated a rationalized therapeutic strategy using a combined systemic treatment with the multifunctional FUS1-nanoparticles and the PDGFR kinase inhibitor imatinib (gleevec) or the Src inhibitor Dasatinib or KX2-391 to simultaneously target the dysregulated PDGFR-Src-PI3K-Akt signaling pathways and suppress tumor cell growth by facilitating apoptosis in human lung cancer cells in vitro and in vivo.

      We have compared the effectiveness of the orally-available Src inhibitor dasatinib (a ATP competitive inhibitor) or KX2-391 (a novel non-competitive inhibitor that interrupts binding of the Src kinase to its substrates) as an single agent or in combination with FUS1-nanopaticles for potentiating their anticancer efficacy in NSCL and SCLC cells. We found that the dasatinib treatment alone showed a moderate level of tumor cell growth arrest and cell viability reduction but a low degree of apoptosis induction in selected NSCLC cells and exhibited a very low degree of tumor cell killing in SCLC cells. In comparison, the KX2 demonstrated a 10-100 fold higher tumor cell killing and apoptosis induction than Dasatinib in more than 20 NSCLC and SCLC cells tested. The ectopic expression by FUS1- nanoparticle-mediated gene transfer in these lung cancer cells markedly enhanced the dasatinib- or KX2-mediated tumor cell killing. The combination treatment with FUS1-nanoparticles and Src inhibitors dramatically reduced their IC50s in NSCLC cells and suppressed NSCLC cells growth through a mechanism of action by a significant induction of apoptosis and the down-regulation of activated EGFR, PI3K, Akt, and Src kinases. Furthermore, the ectopic expression of wt-FUS1 in the PDGFRß-expressing SCLC H128, N417. and NSCLC H358 cell lines inactivated PDGFR oncogenic signaling, as evidenced by a significant reduction in levels of phospho-PDGFRß and downstream phospho-PI3-K and phospho-AKT protein expression, relative to untransfected or lacZ-transfected controls. A combined treatment with FUS1-nanoparticles and the PTK inhibitor imatinib synergistically inhibited growth and induced apoptosis in SCLC and NSCLC cell lines and in preclinical mouse models with N417 SCLC orthotopic lung tumor xenografts.

      Our findings suggest that a combination of the pro-apoptotic FUS1-nanoparticle with novel PDGFR or Src inhibitors targeting the PDGFR-Src-PI3K-Akt signaling pathway that is significantly mutated and predominantly activated in lung cancer cells could sensitize their response to PDGFR and Src inhibitors by more efficiently inhibiting tumor cell proliferation and survival, facilitating apoptosis, and overcoming drug resistance. (This abstract is supported by NIH/NCI Grants SPORE P50CA70907 and RO1CA116322).