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J.C. Lee



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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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      P1.05-008 - The HSP 90 inhibitors suppress cell growth by suppression of ALK and TGF-beta1 signaling in crizotinib-resitant H2228 cells by Epithelial to mesenchymal transition (ID 2544)

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

      • Abstract

      Background
      Epithelial to mesenchymal transition (EMT) is related with reduced sensitivity to many chemotherapeutic drugs including EGFR tyrosine kinase inhibitors. We investigated whether EMT also could contribute to the resistance to crizotinib and there are other therapeutic options overcoming EMT-mediated resistance.

      Methods
      We established a crizotinib-resistant subline (H2228/CR), which was derived from the parental H2228 cell line by long-term exposure to increasing concentration of crizotinib. Characteristics related with EMT including morphology, EMT marker proteins and cellular mobility were analyzed. We examined whether the induction of EMT affect sensitivity to Hsp90 inhibitors.

      Results
      Compared with the H2228 cell, the growth of H2228/CR cells was independent on EML4-ALK, and they showed cross-resistance to TAE-684 (a 2[nd]-generation ALK inhibitor). Phenotypic change of a spindle-cell shape was found in H2228/CR, which was accompanied by a decrease of E-cadherin and an increase of vimentin and AXL. In addition, they showed the increased secretion and expression of TGF-β1. The capability of invasion and migration was dramatically increased in H2228/CR cells. TGF-b1 treatment for 72 h in parental H2228 cells induced reversible EMT leading to crizotinib-resistance while this was reversed through the removal of TGF-β1. Suppression of vimentin by siRNA treatment in H2228/CR cells restored the sensitivity to crizotinib. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitors similar to parental cells, H2228. HSP90 inhibition resulted in downregulation of TGF-β receptor II in addition to ALK.

      Conclusion
      EMT should be considered as one of possible acquired resistant mechanisms to crizotinib and HSP90 inhibitors can be a promising therapeutic option for EMT-mediated resistance.

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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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      P1.10-046 - Heat shock protein 70 as a predictive maker in patients with platinum-based adjuvant chemotherapy in resected non-small cell lung cancer (ID 2735)

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

      • Abstract

      Background
      Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We hypothesized that heat shock protein 70 (Hsp70) would be a biomarker for selecting patients for adjuvant chemotherapy, and evaluated the prognostic or predictive significance of Hsp70 in patients with surgically resected NSCLC.

      Methods
      Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA between January 1996 and December 2010 were included. We conducted immunohistochemical staining for Hsp70 on surgical specimens and compared survival rates depending on whether of Hsp70 expression and adjuvant platinum-based chemotherapy.

      Results
      Among 327 patients, Hsp70 expression was positive in 220 (67.3%). For the patients without adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for the patients with adjuvant chemotherapy, patients with Hsp70-positive tumors had longer disease-free survival (DFS; 82.4 vs. 29.7 months; P = 0.004) as well as longer overall survival (OS; 101.9 vs. 73.4 months, P = 0.12) than those with Hsp70-negative tumors. Multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death than those with Hsp70-negative tumors after adjusting for age, gender, performance status, pathologic stage, and histologic types in adjuvant chemotherapy group (DFS: adjusted hazard ratio [AHR], 0.54; 95% CI, 0.36 to 0.80; P = 0.002; OS: AHR, 0.66; 95% CI, 0.42 to 1.05; P = 0.08). Figure 1

      Conclusion
      Hsp70 is a positive predictive factor in completely resected NSCLC and Hsp70-positive tumors seem to benefit from adjuvant platinum-based chemotherapy.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-006 - The selective regulation of EGFR mutants by C-terminus of Hsc70-interacting-protein(CHIP) in lung adenocarcinoma (ID 1116)

      10:55 - 11:12  |  Author(s): J.C. Lee

      • Abstract
      • Slides

      Background
      Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are response predictive markers for the treatment of lung adenocarcinoma by using EGFR tyrosine kinase inhibitors. The stability of EGFR is dependent on its interaction with heat shock protein 90 (Hsp90), and Hsp90 inhibition may induce ubiquitin-mediated degradation of EGFR proteins. However, the mechanism of EGFR downregulation by HSP90 inhibition remains unclear. Here, we report a novel interaction between EGFR mutants and the E3 ubiquitin ligase C-terminus of Hsp70-interacting protein (CHIP), which can ubiquitinate and destabilize EGFR mutants

      Methods
      Cell culture, transfection and drug treatments NSCLC (A549, H358, H827, and PC9 cells) and Chinese hamster ovarian (CHO) cell lines used in the study were obtained from ATCC. Transfections of different DNA constructs were performed using Lipofectamine 2000 or PolyJet Western blot and immunoprecipitation Cells were then chilled on ice, washed twice with ice-cold PBS, and lysed in a buffer. Protein concentrations were determined using a Bradford assay kit. Equal amounts of protein (20 μg) in cell lysates were separated by SDS-PAGE, transferred to membranes, immunoblotted with specific primary and secondary antibodies, and detected by chemiluminescence with the enhanced chemiluminescence detection reagents. Cell viability assay After trasnfection with or without CHIP, cell metabolic activity was determined every 24 hours by using the CCK-8 (Dojindo, Gaithersburg, MD) colorimetric assay according to the manufacturer’s instructions. Cell cycle analysis by FACS Cells were seeded in 6-well plate and incubated overnight before transfection. After harvest at 48 h following transfection, cells were washed twice with pre-chilled PBS and resuspended in PBS (100 μL) at a concentration of 1 × 106 cells/mL. Cell cycle analysis was performed using the Coulter DNA PrepTM Reagents Kit. Xenograft studies A549 and PC9 cells were cultured as monolayers, trypsinized and resuspended in an equal volume of PBS at 5 × 107 per ml, respectively. BALB/c female nu/nu mice (5 weeks of age) were given bilateral subcutaneous injections of 5 × 106 (0.1 ml). Tumor growth was monitored twice each week by measuring the tumor size using calipers

      Results
      In CHO cells expressing either WT or mutant EGFR, the expression of the EGFR mutants L858R, G719S, and L747_E749del A750P was inhibited following overexpression of CHIP, whereas WT EGFR expression was not diminished in CHIP transfected cells. In a pull-down assay, CHIP interacted with G719S and del L747_E749del A750P, but not L858R, and simultaneously induced the ubiquitination and proteasomal degradation of its proteins. Similarly, the expression of mutant EGFR proteins in the non-small cell lung cancer cell line PC9 was also diminished by CHIP-mediated ubiquitination and degradation relative to WT EGFR. In EGFR mutant cell lines, CHIP inhibited cell proliferation as well as the depletion of phosphorylated Akt. In addition, CHIP inhibited the tumor growth of PC9 cells in xenografts of CHIP-overexpressing stable cell lines.

      Conclusion
      These data suggest that CHIP-induced ubiquitination of EGFR mutants may be responsible for EGFR regulation in lung adenocarcinoma and provide evidence that CHIP could be a novel E3 ligase for EGFR mutants.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-010 - Phase I study of HM61713, a novel epidermal growth factor receptor (EGFR) mutant selective inhibitor, in non-small cell lung cancer (NSCLC) patients having an activating EGFR mutation but failed to prior EGFR tyrosine kinase inhibitor (TKI) therapy. (ID 1048)

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

      • Abstract

      Background
      NSCLC patients having an activating EGFR mutation initially responded well to EGFR TKI but most of them experienced progressive disease due to various resistance mechanisms including T790M (~50% of cases) mutation. HM61713 is an orally active, novel EGFR mutant selective inhibitor showing a strong anticancer activity in many lung cancer cell lines including T790M mutation harboring cell line. Therefore, HM61713 might provide the potential clinical benefit to those who have an activating EGFR mutation but have failed previous EGFR TKI treatment.

      Methods
      This is a phase I study using a standard 3+3 dose escalation scheme. NSCLC Patients with activating EGFR mutation and progressed after at least 2 prior chemotherapy regimens including EGFR TKI were eligible. The objective of this study is to determine the recommended phase II dose as well as to assess the preliminarily efficacy.

      Results
      To date, a total of 23 patients were treated with at doses of 75-250 mg/day. One patient at a dose of 200 mg/day experienced grade 3 drug induced idiosyncrasy and grade 4 elevation of amylase. The drug induced idiosyncrasy was skin rash of non-EGFR TKI type. The most common drug-related adverse events were desquamation, diarrhea, pruritus, and nausea; most were grade 1 or 2. The maximum tolerated dose (MTD) and recommended phase II dose were not determined yet. Plasma concentration of HM61713 reached the peak 2-4 hr after administration and declined with the half-life of 8-12 hr. Among 21 evaluable patients, 2 patients achieved partial response (PR) and one of them had confirmed T790M mutation while 12 patients had stable disease (SD) including 11 patients showed tumor shrinkage. Accrual to this study is ongoing and updated data will be presented at the meeting.

      Conclusion
      HM61713 showed good safety profile and promising anticancer activity in NSCLC patients with EGFR mutation who failed to prior EGFR TKI therapy. These results support the therapeutic potential of HM61713 for NSCLC patients with activating EGFR mutations after development of resistance to EGFR TKI therapy.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-027 - Selection of patients with adenocarcinoma of the lung for Gefinitib by FDG PET metabolic response (ID 1628)

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

      • Abstract

      Background
      Gefitinib is the standard therapy for non-small cell lung cancer patients harboring activating EGFR mutation. However, there are some limitations; 1) we need sufficient tumor tissue to analyze EGFR mutation test; 2) we have to wait result of the test, causing delay of treatment; and 3) we can evaluate the response 4 weeks later but some of the patients do not respond to EGFR TKIs even though they have an activating EGFR mutation. Therefore, we investigated the role of FDG PET as a method overcoming the limitations to evaluate the response to EGFR TKIs.

      Methods
      Key eligibility is as follows; advanced/metastatic adenocarcinoma of the lung; never smoker; no prior chemotherapy; ECOG PS of 0-1; and main lesion > 2cm. The patients performed two times of FDG PET; before starting gefitinib and after 7 days of gefitinib 250mg/d therapy. If % decrease of peak standardized uptake value (pSUV) of main lesion was 20% or more, gefitinib was continued till progression (Group A). After 6 weeks of the treatment, conventional response evaluation using chest CT was done. But, if % decrease of pSUV less than 20% or increase, treatment changed from gefitinib to pemetrexed/cisplatin (Group B). Primary endpoint was to see the response rate of gefitinib in the patients of Group A. EGFR mutation test using direct sequencing method was also performed but the result was not available or unknown to investigators before the report of second PET result.

      Results
      Between Apr 2012 and Apr 2013, 50 patients participated. After 7 day-treatment of gefitinib, 28 out of 50 patients showed decrease of pSUV of main lesion ≥ 20 % (47.4±15.8%) (Group A). Out of the 28 patients in Group A, 27 patients were evaluable; PR in 24 (85.7%), SD in 2 and PD in 1 (Table). EGFR mutation was identified later in 24 patients (85.7%) and 4 patients showed wild type EGFR with 2 PRs, 1 PD and 1 NE. Twenty-two patients showed decrease of pSUV < 20 % or increase (-0.3±15.3%). Interestingly, 19 patients (86.4%) had wild type EGRF while two had an activating EGFR mutation. One patient who showed mutated EGFR in Group B was given gefitinib continuously as physician’s decision. But the patient did progressed after all.

      Group A (gefitinib, n=28) Group B (pem/cis, n=22)
      Response EGFR mutation EGFR mutation
      Postive (n=24) Negative (n=4) Total (n=28) Postive (n=2) Negative (n=19) NE (n=1) Total (n=22)
      CR - - 0 - - - 0
      PR 22 2 24 (85.7%) 1 13 - 14 (63.6%)
      SD 2 - 2 (7.1%) - 4 - 4 (18.2%)
      PD - 1 1 (3.6%) - 1 - 1 (4.5%)
      NE - 1 1 (3.6%) 1 1 1 3 (13.6%)

      Conclusion
      The % decrease of pSUV of ≥ 20 % after 7 days of gefitinib treatment would be a good indicator to predict tumor response to EGFR TKI therapy in this clinical setting.