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E.H. Seeley

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    MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA07.09 - Mass Spectrometry Profiling and Imaging Platform for Novel Precision Drug Resistance Biomarkers Discovery in EML4-ALK Lung Adenocarcinoma (ID 6274)

      11:00 - 12:30  |  Author(s): E.H. Seeley

      • Abstract
      • Presentation
      • Slides

      Drug resistance emergence is a daunting obstacle that limits long-term outcome benefits in precision cancer therapy. Mechanism of the initial emergence of molecular tumor resistance is still not fully understood. Recently, we identified an early precision drug escape mechanism with adaptive tumor cellular reprogramming emerging within days after drug initiation. Here we present a mass spectrometry imaging (MSI) approach to profile the biomolecular changes emerging within residual drug resistant tumor cells under precision ALK inhibitor (ALK-i) treatment.

      EML4-ALK fusion (ALK+) H3122 lung adenocarcinoma xenograft as well as an ALK+ patient biopsy-derived cell line (Ma-ALK001.S) were adopted for the MSI studies. MSI was carried out on FFPE tissues to compare peptide profiles between control tumors and 7- and 14-day ALK-i treated tumors using a histology guided mass spectrometry approach. Additionally, frozen control and ALK-i treated tumors were subjected to full section MSI to determine the ALK-i drug distribution as well as the changing landscape of lipids and metabolites. In parallel, Ma-ALK001.S cell line was treated with alectinib (ALK-i) in culture with samples collected at 0 hr, 8 hr, 3 days, 7 days, and 14 days. Cells were subjected to both MALDI-MS profiling analysis and Laser Ablation Electrospray Ionization (LAESI)-MS analysis. Statistical analyses were performed using MarkerLynx and SCiLS.

      ALK+ H3122 lung adenocarcinoma murine xenograft model in vivo under treatment with/without ALK-i TAE684 was used in MSI studies at treatment day 0, day 7 and day 14, during tumor response. Pairwise and 3-way Wilcoxon rank sum tests were carried out and a Bonferroni correction applied. The greatest number of significant peaks were observed between day 0 and day 14 (677). Pairwise linear discriminant analysis classification algorithm models were generated resulting in over 94% classification accuracy in all comparison. Direct MS/MS fragmentation revealed that ALK-i was detected within the frozen ALK-i dosed tumors in early drug-escape. Several lipids were identified to expression landscape changes emerging under ALK-i. Biomolecular (peptides, lipids, and metabolites) profiling of Ma-ALK001.S cell line using combined MALDI and LAESI MSI analysis was successful, which provided novel insights into the early mechanisms of molecular drug resistance emergence.

      MSI allowed for direct in situ determination of the evolving expression landscape of biomolecules in ALK+ lung cancer under ALK-i precision therapy. These results provide a rationale to advance our MSI profiling studies for biomarkers discovery to gain deeper insights into molecular mechanisms of adaptive precision drug resistance emergence.

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