title: APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.
abstract: Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution.
  
  
  
  We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218-33. ©2017 AACR.See related commentary by Burkard and Weaver, p. 134This article is highlighted in the In This Issue feature, p. 115.
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sansregret
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: James O
authors.initials: JO
authors.lastname: Patterson
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Dewhurst
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-García
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: André
authors.initials: A
authors.lastname: Koch
authors.affiliation: The Francis Crick Institute, London, United Kingdom.|CRUK UCL/Manchester Lung Cancer Centre of Excellence.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: William Chong Hang
authors.initials: WCH
authors.lastname: Chao
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Barry
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Rachael
authors.initials: R
authors.lastname: Instrell
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Way
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Singleton
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Nurse
authors.affiliation: The Francis Crick Institute, London, United Kingdom.|Boehringer Ingelheim, Vienna, Austria.
authors.forename: Mark
authors.initials: M
authors.lastname: Petronczki
authors.affiliation: The Francis Crick Institute, London, United Kingdom.|CRUK UCL/Manchester Lung Cancer Centre of Excellence.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D000072669:Gene Editing / Q000379:methods*; D023281:Genomics / Q000379:methods*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; C577366:CDC27 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome