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J.S. Lee



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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-012 - Paracrine receptor activation by microenvironment as a mechanism of RET inhibitor resistance in CCDC6-RET lung cancer cells (ID 3219)

      09:30 - 16:30  |  Author(s): J.S. Lee

      • Abstract

      Background
      Rearrangement of the proto-oncogene RET is a newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) such as sunitinib, sorafenib, and vandetanib target RET kinase activity, suggesting that the patients with RET fusion genes may be treatable with a kinase inhibitor. However, the mechanisms of resistance to these agents remain largely unknown. Cancer cell microenvironments can critically affect cancer cell behaviors, including drug sensitivity. We determine whether microenvironmental factors trigger RET inhibitor resistance in LC-2/ad cell with CCDC6-RET fusion gene.

      Methods
      We investigated the effects of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) on the susceptibility of CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, sorafenib, vandetanib and E7080)

      Results
      CCDC6-RET lung cancer cell was highly sensitive to RET inhibitors. EGF receptor (EGFR) ligand, EGF, activated EGFR and triggered resistance to sunitinib, E7080, sorafenib and vandetanib by transducing bypass survival signaling through Erk1/2 and Akt. The resistance to RET inhibitors was not induced by EGF in EGFR siRNA-treated cells. EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors even in the presence of EGF. Endothelial cells, which were known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cell to RET inhibitors, an effect inhibited by anti-EGFR antibody (cetuximab). HGF, MET receptor ligand, affected a drug response of sunitinib, not sorafenib, vandetanib and E7080.

      Conclusion
      Paracrine receptor activation by ligand from the microenvironment may trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with RET inhibitors. LC-2/ad cell line was sensitive to E7080, which inhibited RET and its downstream targets. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-003 - Alteration of the E-cadherin/β-catenin complex predicts poor response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment (ID 161)

      09:30 - 16:30  |  Author(s): J.S. Lee

      • Abstract

      Background
      Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50% of patients, but the remaining mechanisms are unknown.

      Methods
      Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification.

      Results
      Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p=0.005) and shorter overall survival (p=0.059). Additionally, β-catenin alteration was associated with a poor ORR (p=0.012). In the metastatic tumours, 3 cases (37.5%) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss, and 2 cases (25.0%) demonstrated MET/EGFR amplification.

      Conclusion
      Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-027 - Phase I studies of HM781-36B, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in patients with advanced solid tumor and the therapeutic potential in patients with advanced non-small cell lung cancer (NSCLC) (ID 2029)

      09:30 - 16:30  |  Author(s): J.S. Lee

      • Abstract

      Background
      HM781-36B is an irreversible pan-HER TKI, which showed a strong anticancer activity in many cell lines, including epidermal growth factor receptor (EGFR) TKI resistant ones in preclinical studies. Two phase I studies were conducted to determine the maximum tolerated dose (MTD) in patients with advanced solid tumor.

      Methods
      Patients with advanced malignancies refractory to standard therapies were eligible. Standard 3+3 dose escalation scheme was used in two phase I studies; a 2-weeks on / 1-week off schedule and a continuous dosing schedule.

      Results
      A total of 75 patients were enrolled; 55 patients in the 2-weeks on / 1-week off schedule and 20 patients in the continuous dosing schedule. 27 NSCLC patients were enrolled. Among 25 evaluable NSCLC patients, 3 patients achieved partial response (PR) and 10 patients had stable disease (SD). All 3 patients who achieved PR were previously treated with gefitinib, and one of them harbored EGFR T790M mutation. In addition, two of them had been treated with 4 or more regimens. Among 10 SD patients, 5 patients showed some degree of tumor shrinkage. Dose -limiting toxicity (DLT) was grade 3 diarrhea. The MTD was determined as 24 mg/day in the 2-weeks on / 1-week off schedule and 18 mg/day in the continuous dosing schedule. The recommended phase II dose was 16 mg/day (continuous) on the basis of toxicity, pharmacokinetic and pharmacodynamic profiles. Two phase II studies of HM781-36B are ongoing in NSCLC patients with previously EGFR TKI treated and EGFR TKI naive, respectively.

      Conclusion
      HM781-36B showed good safety profile and anticancer activity in NSCLC patients in two phase I studies. Effectiveness in the gefitinib refractory and heavily pretreated patients supported the potential of HM781-36B as a therapeutic agent for NSCLC.