Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

M. Sonobe



Author of

  • +

    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      P2.04-097 - Vinorelbine Resistance in Lung Cancer; Role of Focal Adhesion Signaling Pathways (ID 2569)

      09:30 - 09:30  |  Author(s): M. Sonobe

      • Abstract
      • Slides

      Background:
      Vinorelbine (VRB) combined with cisplatin is a widely used regimen for the treatment of non-small cell lung cancer, but their curative effect is unsatisfactory. The resistance to these drugs is the main cause of chemotherapeutic failure. Several factors are reported to be related with VRB resistance, however their validity remains controversial. In the present study, we compared the gene expression and protein phosphorylation between parental (P) and induced VRB resistant (VR) cell lines to elucidate candidate mechanisms for VRB resistance.

      Methods:
      First we established VR lung cancer cells (H1299) with the exposure to the graded increase in VRB concentration. Then, transcriptional changes were measured with DNA microarray and pathway analysis by comparing VR line to the parental. Protein expression and its activation in the candidate pathway were examined by western blot analysis. Cell viability about VRB and Src / ABCB1 inhibitors was assessed by ‘WST-8 assays’.

      Results:
      Half-maximum inhibitory concentration (IC50) of VR cells to VRB were 190 times higher than that of parental cells. VR cells had cross resistance to docetaxel and etoposide, but they did not have cross resistance to cisplatin. VR cells highly expressed ABC transporter (ABCB1: fold change = 13.4) and focal adhesion (FA) related genes, such as integrins and underlining molecules (ITGB3: fold change = 3.7, Src: fold change = 1.1). Western blot analysis confirmed the high expression of intergrin β1, β3 and the activation of the FA pathways including Src, and Akt in VR cells. VRB sensitivity in VR cells was recovered with ABCB1 inhibitor (tariquidar: TQD). Although single usage of Src inhibitor (dasatinib: DAS) did not show any effectiveness, TQD and DAS had synergistic effect on VRB sensitivity. VRB IC50 concomitant use with DMSO, DAS 50 nM, TQD 15 nM, and DAS 50 nM + TQD 15 nM were 1261 nM, 1125 nM, 466.5 nM, and 75.58 nM, respectively. Saracatinib (SAR), a dual inhibitor of Src and ABCB1, recovered VRB sensitivity (Fig.).Figure 1



      Conclusion:
      Indeed, ABCB1 is the main cause of VRB resistance and multi-drug resistance in lung cancer. Genome-wide gene expression analyses revealed another candidate, focal adhesion pathways, except for drug efflux in VRB resistance. Our results show the potential of Src inhibitor to overcome these drug resistance.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
    • +

      P3.03-022 - Feasibility of Adjuvant Therapy with S-1 plus Carboplatin Followed by Maintenance Therapy with S-1 for Resected Non-Small-Cell Lung Cancer (ID 470)

      09:30 - 09:30  |  Author(s): M. Sonobe

      • Abstract

      Background:
      The prognosis of patients with locally-advanced stages (II or IIIA) non-small-cell lung cancer (NSCLC) is unsatisfactory, even after complete resection, and the 5-year survival rate is <50%, indicating the need for further improvements in postoperative survival. This multicenter study (the Setouchi Lung Cancer Group Study 0701) aimed to evaluate the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely-resected stage II–IIIA NSCLC.

      Methods:
      Figure 1 Patients received four cycles of S-1 (80 mg/m2/day for 2 weeks, followed by 2 weeks’ rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m2/day for 2 weeks, followed by 1 week’s rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment-completion rate was determined and treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%.



      Results:
      Figure 1 Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment-completion rate was 63.2% (90% CI: 54.4–71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (11.5%), thrombocytopenia (10.3%), and anorexia (2.3%). The 2-year relapse-free survival rate was 59.8%.



      Conclusion:
      We concluded that novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 was feasible and tolerable in patients with completely-resected NSCLC.