RGD Reference Report - Mechanisms promoting escape from mitotic stress-induced tumor cell death. - Rat Genome Database

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Mechanisms promoting escape from mitotic stress-induced tumor cell death.

Authors: Sinnott, Rebecca  Winters, Leah  Larson, Brittany  Mytsa, Daniela  Taus, Patrick  Cappell, Kathryn M  Whitehurst, Angelique W 
Citation: Sinnott R, etal., Cancer Res. 2014 Jul 15;74(14):3857-69. doi: 10.1158/0008-5472.CAN-13-3398. Epub 2014 May 23.
RGD ID: 152998908
Pubmed: PMID:24860162   (View Abstract at PubMed)
PMCID: PMC4102622   (View Article at PubMed Central)
DOI: DOI:10.1158/0008-5472.CAN-13-3398   (Journal Full-text)

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 the molecular underpinnings of the intrinsic resistance of chemo-naïve NSCLC. Here we report that intrinsic resistance to paclitaxel in NSCLC occurs at a cell-autonomous level because of the uncoupling of mitotic defects from apoptosis. 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, which may 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lung non-small cell carcinoma amelioratesISODnai7 (Mus musculus)152998908; 152998908 RGD 
lung non-small cell carcinoma amelioratesIMP 152998908 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dnai7  (dynein axonemal intermediate chain 7)

Genes (Mus musculus)
Dnai7  (dynein axonemal intermediate chain 7)

Genes (Homo sapiens)
DNAI7  (dynein axonemal intermediate chain 7)


Additional Information