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Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma

Mari Masuda1, Wei-Yu Chen2, Akihiko Miyanaga3

  • 1From the ‡Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, 104-0045 Japan; mamasuda@ncc.go.jp.

Molecular & Cellular Proteomics : MCP
|March 20, 2014
PubMed

Insights

High levels of phosphorylated ribosomal protein S6 (p-RPS6 S235/236) indicate resistance to sorafenib in liver cancer (HCC). This finding suggests mTOR inhibitors may treat tumors unresponsive to sorafenib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Sorafenib is a multi-kinase inhibitor used for unresectable hepatocellular carcinoma (HCC).
  • The exact mechanisms of sorafenib action and resistance in HCC remain unclear.
  • Understanding resistance mechanisms is crucial for improving HCC treatment outcomes.

Purpose of the Study:

  • To investigate the signaling pathways associated with sorafenib resistance in HCC.
  • To identify potential biomarkers for predicting HCC response to sorafenib.
  • To explore alternative therapeutic strategies for sorafenib-resistant HCC.

Main Methods:

  • Utilized high-density fluorescence reverse-phase protein arrays to analyze 180 phosphorylation sites across 120 signaling pathways in 23 HCC cell lines.
  • Correlated signaling node activity with sorafenib sensitivity.
  • Validated findings using immunohistochemistry on HCC patient biopsy samples.
  • Performed whole-exon sequencing of kinase genes in resistant cell lines.

Main Results:

  • Phosphorylated ribosomal protein S6 at serine 235/236 (p-RPS6 S235/236) showed the strongest correlation with sorafenib resistance in HCC cells.
  • Elevated p-RPS6 S235/236 levels were confirmed in HCC patients with poor response to sorafenib.
  • Sorafenib-resistant HCC cells exhibited constitutive activation of the mammalian target of rapamycin (mTOR) pathway without identifiable kinase gene alterations.

Conclusions:

  • p-RPS6 S235/236 serves as a potential predictive biomarker for sorafenib unresponsiveness in HCC.
  • The mammalian target of rapamycin (mTOR) pathway is implicated in sorafenib resistance.
  • Targeting the mTOR pathway with inhibitors could be a viable treatment option for sorafenib-resistant HCC.

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