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Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
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Mechanisms promoting escape from mitotic stress-induced tumor cell death

Rebecca Sinnott1, Leah Winters2, Brittany Larson3

  • 1Authors' Affiliations: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill;

Cancer Research
|May 27, 2014
PubMed

Insights

Intrinsic paclitaxel resistance in non-small cell lung cancer (NSCLC) stems from a failure to trigger apoptosis after mitotic defects. Targeting this resistance mechanism could enhance chemotherapy effectiveness for NSCLC patients.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) exhibits poor responses to initial treatments.
  • Intrinsic chemoresistance in NSCLC, unlike acquired resistance, is poorly understood.
  • Paclitaxel resistance in NSCLC is linked to a cell-autonomous mechanism where mitotic defects do not induce apoptosis.

Purpose of the Study:

  • To investigate the molecular basis of intrinsic paclitaxel resistance in NSCLC.
  • To identify factors that enable cancer cells to evade apoptosis despite mitotic stress.
  • To explore therapeutic strategies to overcome paclitaxel resistance in NSCLC.

Main Methods:

  • Genome-wide RNAi screen combined with high-throughput toxicity and live-cell imaging.
  • Utilized a small molecule inhibitor of the APC/cyclosome to prolong mitotic arrest.
  • Investigated the roles of CASC1 and TRIM69 in resistance to spindle poisons.

Main Results:

  • Prolonging mitotic arrest sensitized paclitaxel-resistant NSCLC cells.
  • Identified CASC1 and TRIM69 as novel contributors to resistance against spindle poisons.
  • CASC1 is crucial for microtubule polymerization and spindle assembly checkpoint function.
  • TRIM69 is essential for bipolar spindle formation by associating with spindle poles and promoting centrosomal clustering.
  • RNAi-mediated reduction of CASC1 or TRIM69 inhibited tumor growth in vivo.

Conclusions:

  • Intrinsic paclitaxel resistance in NSCLC is mediated by a permissive mitotic checkpoint that allows survival despite chromosomal instability.
  • CASC1 and TRIM69 play critical roles in this resistance mechanism.
  • Targeting this adaptation by restoring apoptotic responses to mitotic damage offers a potential strategy for treating drug-resistant NSCLC.

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