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V. Bhat

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    MINI 27 - Biology and Other Issues in SCLC (ID 152)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI27.12 - Using a Cell Surface Antibody Screen to Identify Biomarkers of Drug Resistance in Small Cell Lung Cancer (SCLC) (ID 3002)

      16:45 - 18:15  |  Author(s): V. Bhat

      • Abstract
      • Presentation
      • Slides

      SCLC is an aggressive malignancy that shows dramatic clinical responses in 70% of cases to platinum-based chemotherapy in the first line setting, while the remainder have de novo treatment resistance. Of initial treatment responders, almost all will relapse with drug-resistant disease within months of initial therapy. From a clinical perspective, the emergence of drug resistance remains one of the most important barriers to improving SCLC patient outcomes. Better models of in vitro and in vivo drug resistance are therefore required. Cell surface markers are proteins expressed on the outer surface of cells that can identify specific cell types and biologic states. Surface markers represent an attractive class of biomarkers in SCLC: 1) they are independent of cellular transport mechanisms that are known to play a role in SCLC drug resistance; and 2) they can be readily accessed for diagnostic and therapeutic purposes using commercial antibodies.

      NCI-H69 is a classic SCLC cell line derived from a patient prior to systemic treatment, and is chemotherapy sensitive. H69AR is an anthracycline-resistant derivative cell line generated through serial culture of NCI-H69 in increasing concentrations of Adriamycin. H69AR is also cross-resistant to other cytotoxic drugs commonly used to treat SCLC. We performed a pilot screen in both cell lines in duplicate using a human cell surface marker panel containing Alexa Fluor 647-conjugated antibodies against 242 unique cell surface proteins. High-throughput multiplexed flow-cytometry was performed to generate cell surface expression profiles for each antibody in each cell line.

      A total of 53 markers were expressed in at least 20% of cells in either cell line, with 22 positive markers shared by both cell lines including CD44. NCI-H69 was uniquely positive for 24 markers including CD56, a neural progenitor marker used commonly to diagnose SCLC. Seven markers were uniquely positive in H69AR including CD9 and some of its known interactors. The percentage H69AR cells positive for each of the 7 markers ranged from 25% to 88%. CD9 is a member of the transmembrane 4 superfamily involved in many cellular processes including differentiation, adhesion, and signal transduction. Eighty-eight percent of H69AR cells were positive for CD9 compared to only 5.4% of H69 cells. CD9 has previously been implicated in a cell adhesion-mediated drug resistance mechanism in unrelated SCLC chemotherapy-resistant cell lines (S. Kohmo et al. Cancer Research 2010).

      Our pilot data provides a proof-of-concept for our surface biomarker screen-based approach to further understand mechanisms of chemotherapy-resistance in SCLC. We have expanded this screen to additional drug-sensitive and drug-resistant SCLC cell line pairs. Results of the expanded screen will be presented at the meeting.

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