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C. Zhu



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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-036 - An EGFR Tyrosine Kinase Inhibitor Sensitive Patient-Derived Lung Cancer Xenograft Model without Classical Sensitizing Mutations (ID 5398)

      14:30 - 15:45  |  Author(s): C. Zhu

      • Abstract

      Background:
      Mutations in the tyrosine kinase (TK) domain of EGFR are oncogenic driver in 10-20% of lung adenocarcinoma (AdC) patients in Western countries. Approximately 90% of EGFR-TK inhibitor (TKI) sensitizing mutations occur as small in-frame deletions in exon 19 or L858R point mutations in exon 21. Recently, novel driver mutations in EGFR with oncogenic and TKI sensitizing activity have been reported. We present here an AdC patient-derived xenograft (PDX) model (PDX12) that is highly sensitive to EGFR-TKI, yet failed to demonstrate classical TKI sensitizing mechanisms.

      Methods:
      Comprehensive genomics profiling was used to characterize the genotype of PDX12, which was established from a resected stage IIIA AdC patient grafted in NGS mouse. The primary human lung cancer cell line (PHLC12) was extracted from its PDX model (PDX12). Aberrant EGFR cell lines used were H3255 (L858R), H2935 (exon 19 deletion), H1975 (L858R and T790M), and H1944 (wild type). Cell viability was assessed after erlotinib treatment at 1nM - 2μM for 72 hours using MTS assay. Levels of EGFR activation in both pre- and post-treatment by Western blot analysis.

      Results:
      PDX12 model had no known oncogenic mutations (EGFR wild type) on exons 18-21 by next-generation sequencing, RT-qPCR, and SISH, but was highly sensitive to EGFR-TKI. The IC50 to erlotinib treatment at 72 hr was 67.13 ± 7.63 nM for PHLC12, compared to 9.70 ± 2.64 nM for H3255, 64.88 ± 8.49 nM for HCC2935, > 2 μM for H1975, and > 2 μM for H1944 EGFR mutant or wild type cells, respectively. Western blot analysis demonstrated a relatively higher molecular weight band for EGFR protein with high expression level in PHLC12 when compared to other lung cancer cell lines. Using RT-qPCR, relative expression level of each EGFR domain (extracellular, tyrosine kinase, and c-terminal domain) in PHLC12 showed no difference compared to EGFR wild type. Phosphorylation status of EGFR in PHLC12 was similar in activity as compared to erlotinib sensitive cell lines.

      Conclusion:
      PHLC12 represents an enigmatic EGFR TKI sensitive lung PDX model without classical TKI sensitizing aberrations. Additional potential mechanisms of EGFR dependency including exon duplication, or post-translational modification of EGFR protein are being investigated.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03b-089 - CD1C in Lung Adenocarcinoma: Prognosis and Cellular Origin (ID 4809)

      14:30 - 15:45  |  Author(s): C. Zhu

      • Abstract

      Background:
      Adaptive immune response is critical for cancer surveillance and elimination. Dendritic cells (DC) arise from a hematopoietic lineage distinct from other leukocytes which play a central role in adaptive immunity. CD1C is expressed in DC, presenting exogenous lipid antigens to T cell receptor to activate “unconventional” T cells. This study aims to evaluate the cellular expression and prognostic value of CD1C.

      Methods:
      The study used 5 gene expression datasets: UHN181 [lung adenocarcinoma (ADC, n=128), squamous cell carcinoma (SqCC, n=43)], GSE30219 (ADC n=81, non-ADC n=138)], and 3 integrated cohorts [non-SqCC NSCLC (n=1106), PRECOG (39 types of cancer, n=~18,000), and TCGA (33 types of cancer, n=11,000)]. Cancer Cell Line Encyclopedia (CCLE) data were used to determine if CD1C was expressed by cancer cell lines. CIBERSORT algorithm was used to estimate immune cell fraction and Cox proportional model was used to evaluate the association of CD1C expression with survival. Immunohistochemistry (IHC) was used to measure protein expression of CD1C.

      Results:
      Except for hematopoietic and lymphoid cancer cell lines, all CCLE cell lines lack CD1C expression. CIBERSORT analysis together with Pearson correlation analyses on the ADC cases in UHN181, the integrated cohort, and GSE30219 showed that CD1C was expressed by DC. IHC showed staining with a dendritic cell shape pattern. However, the staining of CD1C did not overlapped with CD11c staining, suggesting a specific DC subtype. Cox proportional regression revealed that CD1C was significantly prognostic in the UHN181 ADC cohort (HR=0.75, p=0.05) as the training set. When CD1C expression was categorized into 3 equal groups, the risk of death was reduced in high compared to low CD1C expression group (HR=0.55, 95%CI 0.28-1.07, p=0.07). CD1C is protective only in PD-L1 low expression group (n=108, HR=0.37, 95%CI 0.15-0.89, p=0.026). The favorable prognosis associated with CD1C expression was validated in the integrated cohort of non-SqCC NSCLC (HR=0.55, 95% CI 0.43-0.72, p<0.0001), and in GSE30219 ADC cohort (HR=0.30, 95% CI 0.11-0.84, p=0.02). In PRECOG and TCGA datasets, high CD1C expression is significantly good prognostic in all cancer types (p<1×10[-7] and p<0.001, respectively), suggesting a universal protective role of CD1C expression in cancers. CD1C IHC score was highly correlated with CD1C mRNA expression in ADC patients of UHN181 and was prognostic (HR=0.46, 95%CI 0.22-0.96, p=0.039).

      Conclusion:
      CD1C preferentially is expressed on a subset of DCs and higher expression of CD1C is significant protective factor in all cancer types, especially in lung adenocarcinoma