Cancer Res. 2014 May 23. pii: canres.3398.2013. [Epub ahead of print]

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

Sinnott R1, Winters L2, Larson B3, Mytsa D1, Taus P1, Cappell KM4, Whitehurst AW5.

Author information

• 1Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill.
• 2Department of Anesthesiology, University of Colorado.
• 3Wake Forest University School of Medicine.
• 4Department of Medicine, Stanford University.
• 5Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill angelique.whitehurst@utsouthwestern.edu.

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 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 due to the uncoupling of mitotic defects from apoptosis. To identify components that permit escape from mitotic stress-induced death, we employed 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 cancercells.