A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.
Takahiro Oike,Hideaki Ogiwara,Yuichi Tominaga,Ito Kentaro,Osamu Ando,Koji Tsuta,Tatsuji Mizukami,Yoko Shimada,Hisanori Isomura,Mayumi Komachi,Koh Furuta,Shun-ichi Watanabe,Takashi Nakano,Jun Yokota,Takashi Kohno +14 more
TLDR
The results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes.Abstract:
The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-small-cell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes.read more
Citations
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Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type
Leora Witkowski,Jian Carrot-Zhang,Steffen Albrecht,Somayyeh Fahiminiya,Nancy Hamel,Eva Tomiak,David Grynspan,Emmanouil Saloustros,Javad Nadaf,Barbara Rivera,Catherine Gilpin,Ester Castellsagué,Rachel Silva-Smith,François Plourde,Mona Wu,Avi Saskin,Madeleine Arseneault,Rouzan G. Karabakhtsian,Elizabeth A. Reilly,Frederick R. Ueland,Anna Margiolaki,Kitty Pavlakis,Sharon M. Castellino,Janez Lamovec,Helen J. Mackay,Lawrence M. Roth,Thomas M. Ulbright,Tracey A Bender,Vassilis Georgoulias,Michel Longy,Andrew Berchuck,Marc Tischkowitz,Inga Nagel,Reiner Siebert,Colin J.R. Stewart,Jocelyne Arseneau,W Glenn McCluggage,Blaise A. Clarke,Yasser Riazalhosseini,Martin Hasselblatt,Jacek Majewski,William D. Foulkes +41 more
TL;DR: Findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches, and at least one germline or somatic deleterious SMarCA4 mutation in 30 of 32 cases.
Journal ArticleDOI
ARID1B is a specific vulnerability in ARID1A-mutant cancers
Katherine C. Helming,Xiaofeng Wang,Boris G. Wilson,Francisca Vazquez,Jeffrey R. Haswell,Haley E. Manchester,Youngha Kim,Gregory V. Kryukov,Mahmoud Ghandi,Andrew J. Aguirre,Zainab Jagani,Zhong Wang,Levi A. Garraway,William C. Hahn,Charles W. M. Roberts +14 more
TL;DR: It is found that loss of ARID1B in AR ID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells, and is identified as a potential therapeutic target for ARID 1A-mutant cancers.
Journal ArticleDOI
Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers
Gregory R. Hoffman,Rami Rahal,Frank Buxton,Kay Xiang,Gregory McAllister,Elizabeth Frias,Linda Bagdasarian,Janina Huber,Alicia Lindeman,Dongshu Chen,Rodrigo Romero,Nadire Ramadan,Tanushree Phadke,Kristy Haas,Mariela Jaskelioff,Boris G. Wilson,Matthew J. Meyer,Veronica Saenz-Vash,Huili Zhai,Vic E. Myer,Jeffery A. Porter,Nicholas Keen,Margaret E. McLaughlin,Craig Mickanin,Charles W. M. Roberts,Frank Stegmeier,Zainab Jagani +26 more
TL;DR: This study provides important mechanistic insight into the BRM/BRG1 synthetic lethal relationship, shows this finding translates in vivo, and highlights BRM as a promising therapeutic target for the treatment BRG1-mutant cancers.
Journal ArticleDOI
Synthetic lethal therapies for cancer: what's next after PARP inhibitors?
TL;DR: The authors summarize the potential of various novel forms of synthetic lethality to further improve the treatment of patients with cancer and describe a number of other synthetic lethal interactions that have been discovered in cancer.
Journal ArticleDOI
Recurrent SMARCA4 mutations in small cell carcinoma of the ovary
Petar Jelinic,Jennifer J. Mueller,Narciso Olvera,Fanny Dao,Sasinya N. Scott,Ronak Shah,Jianjiong Gao,Nikolaus Schultz,Mithat Gonen,Robert A. Soslow,Michael F. Berger,Douglas A. Levine +11 more
TL;DR: Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT.
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TL;DR: EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers, and TAE684 inhibited the growth of one of three EML4-alk-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis.
Book
Cancer cell lines
TL;DR: 17. Wilms' Tumor and Other Childhood Renal Neoplasms N.Y. Wilson, C.M. Garner, et al.
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