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An activated JAK/STAT3 pathway and CD45 expression are associated with sensitivity to Hsp90 inhibitors in multiple

Huiqiong Lin1, Iryna Kolosenko, Ann-Charlotte Björklund

  • 1Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.

Experimental Cell Research
|December 19, 2012
PubMed

Insights

Hsp90 inhibitors like 17DMAG show differential activity in multiple myeloma (MM). CD45(+) MM cells with activated JAK/STAT3 pathways are sensitive, while CD45(-) cells with PI3K pathway activation are resistant.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Heat shock protein 90 (Hsp90) is crucial for signaling protein activity, including JAK/STAT and PI3K pathways.
  • Hsp90 inhibitors (Hsp90-Is) have shown variable efficacy in multiple myeloma (MM) clinical trials.

Purpose of the Study:

  • To investigate the signaling pathways responsible for differential sensitivity to the Hsp90 inhibitor 17DMAG in MM cell lines and primary cells.
  • To identify biomarkers predicting response to Hsp90 inhibition in MM.

Main Methods:

  • Treatment of MM cell lines and primary MM cells with 17DMAG.
  • Analysis of JAK/STAT3 and PI3K pathway activation.
  • Assessment of CD45 expression levels.
  • Evaluation of apoptosis and caspase-3 activation.
  • Over-expression of STAT3C and Mcl-1 to assess their role in drug resistance.

Main Results:

  • CD45(+) MM cell lines with activated JAK/STAT3 were sensitive to 17DMAG, undergoing apoptosis.
  • CD45(-) MM cell lines dependent on PI3K signaling were more resistant.
  • IL-6 treatment induced CD45 and pSTAT3, sensitizing resistant cells to 17DMAG.
  • Primary MM cells with high CD45 expression showed higher pSTAT3 and increased caspase-3 activation upon 17DMAG treatment.
  • STAT3 inhibition was key to Hsp90-Is' pro-apoptotic effects, while STAT3C over-expression conferred resistance.
  • Mcl-1 down-regulation by 17DMAG was attenuated in STAT3C-expressing cells.

Conclusions:

  • CD45 expression and JAK/STAT3 pathway activation are key determinants of sensitivity to Hsp90 inhibitors in MM.
  • Hsp90 inhibition targets the JAK/STAT3 pathway, leading to apoptosis in sensitive MM cells.
  • High CD45 expression identifies MM patients likely to benefit from Hsp90-I therapy.

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