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A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction
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A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction

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Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer

Xian Li1, Lin-Jiang Tong, Jian Ding

  • 1Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.

Cancer Letters
|September 11, 2013
PubMed

Insights

Combining sunitinib with rapamycin, an mTOR inhibitor, shows significant synergy against non-small cell lung cancer (NSCLC). This combination enhances cell cycle arrest and inhibits tumor angiogenesis, offering a promising new therapeutic strategy for NSCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin (mTOR) is crucial for cell growth and protein synthesis, making it a key target in cancer therapy.
  • Rapamycin and its analogues (rapalogs) are first-generation mTOR inhibitors, but their clinical efficacy is limited.
  • Combinatorial drug strategies are being explored to enhance the anticancer activity of rapamycin.

Purpose of the Study:

  • To develop an unbiased screening platform for discovering novel drug combinations with rapamycin for cancer therapy.
  • To identify clinically available drugs that synergize with rapamycin in non-small cell lung cancer (NSCLC) cells.
  • To establish a mechanistic rationale for the combination of rapamycin and sunitinib in NSCLC treatment.

Main Methods:

  • Systematic binary drug screening platform was employed to identify synergistic drug combinations with rapamycin.
  • The efficacy of rapamycin-sunitinib combination was evaluated in NSCLC cells, assessing cell cycle arrest and mTOR signaling.
  • In vitro and in vivo assays were used to investigate the combination's effect on endothelial cell tube formation and microvessel growth, analyzing VEGF and HIF1α expression.

Main Results:

  • Sunitinib was identified as a clinically available drug that exhibits significant synergy with rapamycin in NSCLC cells.
  • The combination of rapamycin and sunitinib enhanced G1 phase cell cycle arrest, suppressed mTOR signaling, and disrupted the AKT activation feedback loop.
  • Synergistic anti-angiogenic effects were observed, including reduced endothelial cell tube formation and microvessel outgrowth, linked to decreased VEGF and HIF1α levels.

Conclusions:

  • Systematic drug screening can effectively identify novel combinatorial regimens for cancer therapy.
  • The combination of rapalogs and sunitinib presents a promising therapeutic strategy for human NSCLC, supported by mechanistic evidence of enhanced anti-tumor and anti-angiogenic activity.
Keywords:
CombinationNon-small cell lung cancerRapamycinSunitinib

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