Mechanisms promoting escape from mitotic stress-induced tumor cell death

Rebecca Sinnott, Leah Winters, Brittany Larson, Daniela Mytsa, Patrick Taus, Kathryn M. Cappell, Angelique W. Whitehurst

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Non-small cell lung cancer (NSCLC) is notorious for its paltry responses to first-line therapeutic regimens. In contrast to acquired chemoresistance, little is known about themolecular underpinnings of the intrinsic resistance of chemo-naïve NSCLC. Herewe report that intrinsic resistance to paclitaxel in NSCLC occurs at a cell-autonomous level because of the uncoupling ofmitotic defects fromapoptosis. To identify components that permit escape from mitotic stress-induced death, we used a genome-wide RNAi-based strategy, which combines a high-throughput toxicity screen with a live-cell imaging platform to measure mitotic fate. This strategy revealed that prolonging mitotic arrest with a small molecule inhibitor of the APC/cyclosome could sensitize otherwise paclitaxel-resistant NSCLC. We also defined novel roles for CASC1 and TRIM69 in supporting resistance to spindle poisons. CASC1, which is frequently co-amplified with KRAS in lung tumors, is essential for microtubule polymerization and satisfaction of the spindle assembly checkpoint. TRIM69, which associates with spindle poles and promotes centrosomal clustering, is essential for formation of a bipolar spindle. Notably, RNAi-mediated attenuation of CASC1 or TRIM69 was sufficient to inhibit tumor growth in vivo. On the basis of our results, we hypothesize that tumor evolution selects for a permissive mitotic checkpoint, whichmay promote survival despite chromosome segregation errors. Attacking this adaptation may restore the apoptotic consequences of mitotic damage to permit the therapeutic eradication of drug-resistant cancer cells.

Original languageEnglish (US)
Pages (from-to)3857-3869
Number of pages13
JournalCancer Research
Volume74
Issue number14
DOIs
Publication statusPublished - Jul 15 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sinnott, R., Winters, L., Larson, B., Mytsa, D., Taus, P., Cappell, K. M., & Whitehurst, A. W. (2014). Mechanisms promoting escape from mitotic stress-induced tumor cell death. Cancer Research, 74(14), 3857-3869. https://doi.org/10.1158/0008-5472.CAN-13-3398