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NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation

Zhihua Sun1, Qiuhui Li2, Sheng Zhang2

  • 1Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People's Republic of China.

Oncotargets and Therapy
|February 13, 2015
PubMed
Abstract

Insights

NVP-BEZ235 effectively inhibited gefitinib-resistant non-small cell lung cancer growth and migration. This dual phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor works by downregulating the PI3K/AKT/mTOR signaling pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Activating mutations in epidermal growth factor receptors (EGFR) confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs).
  • Acquired resistance to TKIs, such as gefitinib, develops in most non-small cell lung cancer (NSCLC) patients within approximately 10 months.
  • The PI3K/mTOR pathway is implicated in resistance mechanisms to EGFR-TKIs in NSCLC.

Purpose of the Study:

  • To evaluate the therapeutic efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in a gefitinib-resistant NSCLC model.
  • To investigate the impact of NVP-BEZ235 on tumor growth, migration, and the PI3K/AKT/mTOR signaling pathway in resistant NSCLC.

Main Methods:

  • Validated H1975 cell line (harboring EGFR T790M mutation) as a gefitinib-resistant NSCLC model.
  • Assessed in vitro and in vivo anti-tumor effects using MTT and xenograft assays, respectively.
  • Evaluated cell migration using migration assays and analyzed PI3K/AKT/mTOR pathway protein levels via Western blot and immunohistochemistry.

Main Results:

  • NVP-BEZ235 demonstrated significant inhibition of H1975 cell proliferation both in vitro and in vivo.
  • NVP-BEZ235 treatment led to a reduction in H1975 cell migration.
  • The drug attenuated the phosphorylation of key proteins within the PI3K/AKT/mTOR signaling pathway.

Conclusions:

  • NVP-BEZ235 exhibits potent anti-cancer activity against gefitinib-resistant NSCLC.
  • Downregulation of PI3K/AKT/mTOR pathway phosphorylation is the mechanism by which NVP-BEZ235 exerts its therapeutic effect.
  • NVP-BEZ235 represents a promising therapeutic strategy for patients with acquired resistance to EGFR TKIs.
Keywords:
NVP-BEZ235PI3K kinasegefitinib-acquired resistancemTOR

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