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Disruption of the Anaphase-Promoting Complex Confers Resistance to TTK Inhibitors in Triple-Negative Breast Cancer

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Disruption of the Anaphase-Promoting Complex Confers Resistance to TTK Inhibitors in Triple-Negative Breast Cancer Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer K. L. Thua,b, J. Silvestera,b, M. J. Elliotta,b, W. Ba-alawib,c, M. H. Duncana,b, A. C. Eliaa,b, A. S. Merb, P. Smirnovb,c, Z. Safikhanib, B. Haibe-Kainsb,c,d,e, T. W. Maka,b,c,1, and D. W. Cescona,b,f,1 aCampbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7; bPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7; cDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7; dDepartment of Computer Science, University of Toronto, Toronto, ON, Canada M5G 1L7; eOntario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3; and fDepartment of Medicine, University of Toronto, Toronto, ON, Canada M5G 1L7 Contributed by T. W. Mak, December 27, 2017 (sent for review November 9, 2017; reviewed by Mark E. Burkard and Sabine Elowe) TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), ator of the spindle assembly checkpoint (SAC), which delays is a key regulator of the spindle assembly checkpoint (SAC), which anaphase until all chromosomes are properly attached to the functions to maintain genomic integrity. TTK has emerged as a mitotic spindle, TTK has an integral role in maintaining genomic promising therapeutic target in human cancers, including triple- integrity (6). Because most cancer cells are aneuploid, they are negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are heavily reliant on the SAC to adequately segregate their abnormal being evaluated in clinical trials, and an understanding of karyotypes during mitosis. This is evidenced by the fact that the the mechanisms mediating TTKi sensitivity and resistance could inform SAC is often weakened but rarely completely inactivated in cancer the successful development of this class of agents. We evaluated the cells (7–9). Abrogation of the SAC by TTK inhibition results in cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. intolerable levels of genomic instability that are incompatible with CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC cancer cell survival (10, 11). With several TTK inhibitors (TTKis) lines by accelerating progression through mitosis and inducing mitotic currently being evaluated as anticancer therapeutics in clinical segregation errors. We used genome-wide CRISPR/Cas9 screens in trials, a more complete understanding of the mechanisms medi- multiple TNBC cell lines to identify mechanisms of resistance to CFI- ating TTKi sensitivity and resistance could have a significant im- 402257. Our functional genomic screens identified members of the pact by guiding their successful clinical development. anaphase-promoting complex/cyclosome (APC/C) complex, which In this study, we aimed to identify cellular mechanisms of promotes mitotic progression following inactivation of the SAC. resistance to the clinical TTKi CFI-402257. Importantly, we in- Several screen candidates were validated to confer resistance to CFI- vestigated this question in biologically relevant, aneuploid TNBC 402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These cell lines that model one of the principal human malignancies findings extend the observation that impairment of the APC/C enables for which CFI-402257 is being developed. Using genome-wide cells to tolerate genomic instability caused by SAC inactivation, and CRISPR/Cas9 enrichment screens in three TNBC models, we support the notion that a measure of APC/C function could predict found that genetic disruption of anaphase-promoting complex/ the response to TTK inhibition. Indeed, an APC/C gene expression cyclosome (APC/C) components or other genes involved in mitotic signature is significantly associated with CFI-402257 response in breast andlungadenocarcinomacelllinepanels. This expression signature, Significance along with somatic alterations in genes involved in mitotic progres- sion, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis. Using functional genomic screens, we have identified resistance mechanisms to the clinical TTK protein kinase inhibitor (TTKi) CFI-402257 in breast cancer. As this and other TTKi are currently TTK inhibitor | drug resistance | APC/C | CRISPR/Cas9 | breast cancer in clinical trials, understanding determinants of tumor drug re- sponse could permit rational selection of patients for treatment. riple-negative breast cancer (TNBC), characterized by lack of We found that TTKi resistance is conferred by impairing Texpression of estrogen and progesterone receptors or am- anaphase-promoting complex/cyclosome (APC/C) function to plification of HER2, is recognized as an aggressive disease with minimize the lethal effects of mitotic segregation errors. Dis- poor outcomes and short survival in the metastatic setting. While covery of this mechanism in aneuploid cancer cells builds on TNBC is a heterogeneous disease, the majority exhibit high levels previous reports indicating that weakening the APC/C pro- of aneuploidy and a dearth of actionable genetic alterations (e.g., motes tolerance of chromosomal instability in diploid cells. Our focal DNA amplifications or activating point mutations that can work suggests that APC/C functional capacity may serve as a be targeted) (1–3). The latter explains in part the current lack clinically useful biomarker of tumor response to TTKi that of targeted treatment options for this disease, and underscores warrants investigation in ongoing clinical trials. the need for novel treatment strategies. The recurrent somatic changes that occur in TNBC include nearly ubiquitous TP53 Author contributions: K.L.T., J.S., M.J.E., W.B.-a., B.H.-K., T.W.M., and D.W.C. designed mutations, as well as genetic alterations to other tumor sup- research; K.L.T., J.S., M.J.E., W.B.-a., M.H.D., and A.S.M. performed research; A.S.M., P.S., PTEN RB1 BRCA1 and Z.S. contributed new reagents/analytic tools; K.L.T., J.S., M.J.E., W.B.-a., M.H.D., pressors including , , and components of the A.C.E., B.H.-K., T.W.M., and D.W.C. analyzed data; and K.L.T., W.B.-a., B.H.-K., T.W.M., DNA damage response pathway (1). The loss of these critical and D.W.C. wrote the paper. regulators of the cell cycle and genome maintenance contribute Reviewers: M.E.B., University of Wisconsin; and S.E., Université Laval. to the genomic instability characteristic of TNBC, a hallmark The authors declare no conflict of interest. that represents a potential therapeutic vulnerability (4, 5). Published under the PNAS license. Inhibition of TTK protein kinase (TTK), also known as 1 To whom correspondence may be addressed. Email: [email protected] or dave. monopolar spindle 1 (MPS1), has emerged as a promising [email protected]. therapeutic strategy for the treatment of aneuploid tumors, with This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. TNBCs an important focus of clinical development. As a medi- 1073/pnas.1719577115/-/DCSupplemental. E1570–E1577 | PNAS | Published online January 29, 2018 www.pnas.org/cgi/doi/10.1073/pnas.1719577115 Downloaded by guest on September 25, 2021 PNAS PLUS progression confers resistance to CFI-402257 and other TTKis. Our A 132-BM-ADM MDA-MB-436 864-BM-ADM work independently validates and extends findings from a previous 120 *** 120 *** 120 *** study reporting that APC/C dysfunction promotes diploid cell tol- 100 100 100 (min) erability of genomic instability induced by reversine, a chemical 80 80 80 probe that inhibits TTK (12). Furthermore, we report an APC/C ase gene expression signature that is associated with response to CFI- 60 60 60 402257 in breast and lung cancer cell line panels. This genetic sig- 40 40 40 nature represents a promising biomarker for further development 20 20 20 NEBD - Anaph - NEBD NEBD - Anaphase (min) Anaphase - NEBD NEBD - Anaphase (min) Anaphase - NEBD and evaluation in ongoing clinical trials, where its application in 0 0 0 evaluating APC/C function could inform patient selection or predict DMSO CFI-402257 DMSO CFI-402257 DMSO CFI-402257 150nM 150nM 150nM drug response to clinical TTKis. MDA-MB-231 MDA-MB-436 MDA-MB-468 B ER MP LC AB N Results ** ** *** 100 CFI-402257 Accelerates Mitosis and Induces Mitotic Segregation 100 100 Errors and Apoptosis in TNBC. To study the cellular effects of 80 80 80 CFI-402257 in TNBC, we selected three commonly used cell 60 60 60 line models: MDA-MB-231, MDA-MB-468, and MDA-MB-436. Each line is reportedly aneuploid and contains a TP53 mutation 40 40 40 % of Mitoses % of Mitoses % of Mitoses (13), characteristic of clinical TNBC. The SAC functions to 20 20 20 prevent anaphase onset until all chromosomes are sufficiently 0 0 0 attached to the mitotic spindle, thereby ensuring proper chro- DMSO CFI-402257 DMSO CFI-402257 DMSO CFI-402257 mosome segregation during mitosis (6). TTK inhibition causes 150nM 150nM 150nM SAC inactivation and premature onset of anaphase with im- C DMSO 100nM 400nM properly segregated chromosomes. To assess the effects of TTK MDA-MB-231 MDA-MB-436 MDA-MB-468 100 100 100 inhibition on mitotic timing, live-cell microscopy was used to 0.33 4.41 1.39 80 1.28 80 8.52 80 3.36 measure the time from nuclear envelope breakdown (NEBD) to 18.6 43.1 49.7 onset of anaphase. CFI-402257 treatment (150 nM) significantly 60 60 60 reduced mitotic timing by twofold to threefold in all three cell 40 40 40 A lines (Fig. 1 ). As expected, scoring of mitotic cells identified 20 20 20 significantly more mitotic errors (e.g., lagging chromosomes, Mode To Normalized 0 0 0 anaphase bridges, and multipolar divisions) in CFI-402257– 103 104 103 104 103 104 treated compared with DMSO control-treated cells (Fig.
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