Author of

• 10525

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  P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10537

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    P1.02-012 - Paracrine receptor activation by microenvironment as a mechanism of RET inhibitor resistance in CCDC6-RET lung cancer cells (ID 3219)

    09:30 - 09:30  |  Author(s): S.U. Moon
    • Abstract

    Background
    Rearrangement of the proto-oncogene RET is a newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) such as sunitinib, sorafenib, and vandetanib target RET kinase activity, suggesting that the patients with RET fusion genes may be treatable with a kinase inhibitor. However, the mechanisms of resistance to these agents remain largely unknown. Cancer cell microenvironments can critically affect cancer cell behaviors, including drug sensitivity. We determine whether microenvironmental factors trigger RET inhibitor resistance in LC-2/ad cell with CCDC6-RET fusion gene.

    Methods
    We investigated the effects of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) on the susceptibility of CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, sorafenib, vandetanib and E7080)

    Results
    CCDC6-RET lung cancer cell was highly sensitive to RET inhibitors. EGF receptor (EGFR) ligand, EGF, activated EGFR and triggered resistance to sunitinib, E7080, sorafenib and vandetanib by transducing bypass survival signaling through Erk1/2 and Akt. The resistance to RET inhibitors was not induced by EGF in EGFR siRNA-treated cells. EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors even in the presence of EGF. Endothelial cells, which were known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cell to RET inhibitors, an effect inhibited by anti-EGFR antibody (cetuximab). HGF, MET receptor ligand, affected a drug response of sunitinib, not sorafenib, vandetanib and E7080.

    Conclusion
    Paracrine receptor activation by ligand from the microenvironment may trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with RET inhibitors. LC-2/ad cell line was sensitive to E7080, which inhibited RET and its downstream targets. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.