EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Rearrangements of the proto-oncogene rearranged during transfection (RET) are emerging as key driver mutations in lung adenocarcinoma.
• Tyrosine kinase inhibitors (TKIs) targeting RET kinase activity offer a potential treatment strategy for patients with RET fusion-positive lung cancer.
• Mechanisms underlying resistance to RET inhibitors are not well understood.

Purpose of the Study:

• To investigate whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) induce resistance to RET inhibitors in lung cancer cells harboring CCDC6-RET fusions.
• To elucidate the signaling pathways involved in EGF-mediated resistance to RET inhibitors.

Main Methods:

• Utilized the LC-2/ad cell line, which possesses a CCDC6-RET fusion gene.
• Assessed the impact of EGF and HGF on the sensitivity of these cells to various RET inhibitors, including sunitinib, E7080, vandetanib, and sorafenib.
• Investigated the role of epidermal growth factor receptor (EGFR) signaling and employed EGFR-TKIs and other EGFR-targeting agents.

Main Results:

• CCDC6-RET lung cancer cells demonstrated high sensitivity to RET inhibitors.
• EGF activated EGFR, leading to resistance against multiple RET inhibitors by activating bypass survival signaling pathways (ERK and AKT).
• Endothelial cells, producing EGF, reduced RET inhibitor sensitivity; this effect was mitigated by EGFR inhibition (siRNA, cetuximab, gefitinib). HGF showed minimal impact.

Conclusions:

• EGF is identified as a mediator of resistance to RET inhibitors in CCDC6-RET lung cancer.
• Endothelial cells may contribute to RET inhibitor resistance through EGF secretion.
• EGFR-targeted therapies, in combination with RET inhibitors like E7080, may enhance treatment efficacy for RET-positive lung cancer patients.