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Control of the MYC-eIF4E axis plus mTOR inhibitor treatment in small cell lung cancer

Masaru Matsumoto1, Masahiro Seike2, Rintaro Noro3

  • 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan. s7062@nms.ac.jp.

BMC Cancer
|April 18, 2015
PubMed
Abstract

Insights

Mammalian target of rapamycin (mTOR) inhibitors show limited efficacy in small cell lung cancer (SCLC). The study identified MYC and eukaryotic translation initiation factor 4E (eIF4E) as key drivers of everolimus resistance in SCLC, suggesting targeting this axis could improve treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammalian target of rapamycin (mTOR) inhibitors demonstrate anti-tumor activity in various cancers, including renal cell carcinoma, pancreatic neuroendocrine cancer, and breast cancer.
  • The efficacy and resistance mechanisms of mTOR inhibitors in small cell lung cancer (SCLC) remain incompletely understood.

Purpose of the Study:

  • To investigate the anti-tumor effects of mTOR inhibitors in SCLC cell lines.
  • To elucidate the molecular mechanisms underlying resistance to mTOR inhibitors in SCLC.

Main Methods:

  • Seven SCLC cell lines were treated with three mTOR inhibitors, including everolimus, and their sensitivity was assessed using MTS assays.
  • Gene-chip analysis, receptor tyrosine kinases (RTK) array, and Western blotting were employed to identify resistance-associated molecules.
  • RNA interference (siRNA) was used to investigate the role of MYC and eukaryotic translation initiation factor 4E (eIF4E) in everolimus resistance.

Main Results:

  • Only SBC5 cells exhibited sensitivity to everolimus.
  • Two everolimus-resistant SBC5 cell lines (SBC5 R1 and SBC5 R10) were established.
  • Overexpression of SPP1 and MYC was observed in resistant cells. High eIF4E levels correlated with resistance.
  • MYC siRNA reduced eIF4E phosphorylation, indicating an mTOR-independent pathway. Silencing MYC or eIF4E resensitized resistant cells to everolimus.

Conclusions:

  • Eukaryotic translation initiation factor 4E (eIF4E) plays a significant role in everolimus resistance in SCLC.
  • A link between MYC and mTOR-independent eIF4E activation contributes to everolimus resistance.
  • Targeting the MYC-eIF4E axis represents a potential therapeutic strategy to enhance everolimus efficacy in SCLC.

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