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Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response

Timothy G Whitsett1, Ian T Mathews, Michael H Cardone

  • 1Translational Genomics Research Institute, 445 N. Fifth St., Suite 400, Phoenix, AZ 85004. twhitsett@tgen.org.

Molecular Cancer Research : MCR
|January 29, 2014
PubMed
Abstract

Insights

Therapeutic resistance in non-small cell lung cancer (NSCLC) is linked to the TWEAK-Fn14 pathway, which upregulates Mcl-1. Targeting Mcl-1 offers a new strategy to overcome treatment resistance in NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Therapeutic resistance to chemotherapy, radiotherapy, and TKIs is a major challenge in non-small cell lung cancer (NSCLC) treatment.
  • The molecular mechanisms underlying therapeutic resistance in NSCLC are not fully understood.
  • The TNF-like weak inducer of apoptosis (TWEAK)-FGF-inducible 14 (TNFRSF12A/Fn14) signaling pathway promotes cancer cell survival via NF-κB activation.

Purpose of the Study:

  • To investigate the role of the TWEAK-Fn14 signaling axis in NSCLC therapeutic resistance.
  • To determine the involvement of myeloid cell leukemia sequence 1 (MCL1/Mcl-1) in TWEAK-Fn14-mediated survival.
  • To evaluate Mcl-1 as a potential therapeutic target for overcoming NSCLC resistance.

Main Methods:

  • Correlation analysis of Mcl-1 and Fn14 expression with NSCLC tumor stage and patient prognosis.
  • TWEAK stimulation of NSCLC cells to assess NF-κB activation and Mcl-1 protein expression.
  • Assessment of chemo- and radioresistance in NSCLC cells following Mcl-1 modulation (siRNA or pharmacologic inhibition with EU-5148).
  • Evaluation of EU-5148 efficacy across a panel of NSCLC cell lines.
  • Comparative analysis of TWEAK-induced survival inhibition by targeting Mcl-1 versus Bcl-2/Bcl-xL.

Main Results:

  • Mcl-1 expression positively correlated with Fn14 expression, advanced NSCLC stage, and poor prognosis.
  • TWEAK stimulation induced NF-κB-dependent Mcl-1 expression, conferring chemo- and radioresistance.
  • Mcl-1 depletion or inhibition (EU-5148) sensitized NSCLC cells to cisplatin and radiation, and inhibited survival across multiple cell lines.
  • Inhibition of Bcl-2/Bcl-xL showed minimal impact on TWEAK-induced NSCLC cell survival.

Conclusions:

  • The TWEAK-Fn14 signaling pathway promotes NSCLC cell survival and therapeutic resistance by upregulating Mcl-1.
  • Mcl-1 is a critical mediator of TWEAK-Fn14 prosurvival signaling in NSCLC.
  • Targeting the TWEAK-Fn14 axis and Mcl-1 presents a promising therapeutic strategy for NSCLC.

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