title: Mechanisms promoting escape from mitotic stress-induced tumor cell death.
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 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.
authors.affiliation: Authors' Affiliations: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sinnott
authors.affiliation: Department of Anesthesiology, University of Colorado, Aurora, Colorado; and.
authors.forename: Leah
authors.initials: L
authors.lastname: Winters
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, North Carolina;
authors.forename: Brittany
authors.initials: B
authors.lastname: Larson
authors.affiliation: Authors' Affiliations: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill;
authors.forename: Daniela
authors.initials: D
authors.lastname: Mytsa
authors.affiliation: Authors' Affiliations: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill;
authors.forename: Patrick
authors.initials: P
authors.lastname: Taus
authors.affiliation: Department of Medicine, Stanford University, Stanford, California.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Cappell
authors.affiliation: Authors' Affiliations: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill; angelique.whitehurst@utsouthwestern.edu.
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D000070584:Tripartite Motif Proteins; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000070584:Tripartite Motif Proteins; C579345:TRIM69 protein, human; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel