Author of

• 25913

  +

  MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Small Cell Lung Cancer/NET
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD

  • 26149

    +

    MA22.02 - Activation of MAPK Suppresses Neuroendocrine Transcription Factors and Causes Transdifferentiation of Small Cell Lung Cancer (ID 14051)

    15:20 - 15:25  |  Author(s): William Lockwood
    • Abstract
    • Presentation
    • Slides

    Background
    

    Gene alterations involved in activating signaling through receptor tyrosine kinases/RAS/RAF/MEK/ERK pathway are extremely rare in small cell lung cancer (SCLC). In addition, EGFR expression is lost during the histological reprogramming of EGFR mutation-positive lung adenocarcinoma (LUAD) to SCLC, despite the cancer retaining the original EGFR mutation. These observations imply that signaling through mitogen-activated protein kinases (MAPKs) - critically important in non-small cell lung cancer - might be detrimental in SCLC biology. Here we investigated the impact of induction of two mutated oncogenic proteins, EGFR^L858R and KRAS^G12V_, the most common drivers of LUAD, on the phenotype and signaling profiles of SCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    EGFR^L858R or KRAS^G12V were aberrantly expressed in an inducible manner in three SCLC cell lines (H2107, H82, and H524). The effects of induction of these oncogenes were determined through cell viability analysis and Western blotting analysis particularly focusing on the regulation of master neuroendocrine transcription factors such as insulinoma-associated protein 1 (INSM1), POU class 3 homeobox 2 (BRN2), achaete-scute hologue 1 (ASCL1), and neurogenic differentiation factor 1 (NEUROD1). Genome-wide expression profiles were assessed in a longitudinal manner after oncogene induction and specific gene sets driven by MAPK activation in each SCLC cell line were defined.

    4c3880bb027f159e801041b1021e88e8 Result
    

    INSM1 and BRN2 were expressed in all the SCLC cell lines assessed. ASCL1 was expressed only in H2107 (classic type). Alternatively, NEUROD1 was expressed in the variant type SCLC cell lines, H82 and H524. Induction of mutant-EGFR or -KRAS resulted in different cell viability according to cell lines: H82 cells showed higher proliferation rate and the others showed lower proliferative ability. Furthermore, induction of these oncogenes caused transition from suspension to adherent phenotype in all the three cell lines. Importantly, EGFR/KRAS induction downregulated neuroendocrine transcription factors and these effects were more strongly observed after KRAS induction than after EGFR induction, which was concordant with the difference in degrees of phospho-ERK1/2 upregulation after induction of these mutant-oncogenes. Notably, treatment with SCH772984, an ERK1/2 inhibitor, rescued the repression of neuroendocrine factors by KRAS induction. Gene expression profiling is currently underway to reveal specific factors mediating ERK induced suppression of neuroendocrine programs.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Activation of the RAS/RAF/MEK/ERK pathway causes phenotypic transition in SCLC growing in suspension to the adherent phenotype and suppresses neuroendocrine differentiation. Thus, ERK signaling has an fundamental role in repression of neuroendocrine differentiation programs and may be important in regulating histological transversion of SCLC to and from NSCLC with implications to drug resistance.

    6f8b794f3246b0c1e1780bb4d4d5dc53

    Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

• 24750

  +

  MS01 - Cancer Pathways, Targeted Therapy and Resistance (ID 780)

  • Event: WCLC 2018
  • Type: Mini Symposium
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 F

  • 24752

    +

    MS01.02 - Targeting Negative Feedback Regulators to Hyperactivate Oncogenic Signaling (ID 11402)

    10:50 - 11:10  |  Presenting Author(s): William Lockwood
    • Abstract
    • Presentation
    • Slides

    Abstract not provided

    Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.