PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Srinivas, Upadhyayula Sai; Tay, Norbert S. C.; Jaynes, Patrick; Anbuselvan, Akshaya; Ramachandran, Gokula Krishnan; Wardyn, Joanna D.; Hoppe, Michal Marek; Hoang, Phuong Mai; Peng, Yanfen; Lim, Sherlly; Lee, May Yin; Peethala, Praveen C.; An, Ömer; Shendre, Akshay; Tan, Bryce W.Q.; Jemimah, Sherlyn; Lakshmanan, Manikandan; Hu, Longyu; Jakhar, Rekha; Sachaphibulkij, Karishma; Lim, Lina H.K.; Pervaiz, Shazib; Crasta, Karen; Yang, Henry; Tan, Patrick; Liang, Chao; Ho, Lena; Khanchandani, Vartika; Kappei, Dennis; Yong, Wei Peng; Tan, David S.P.; Bordi, Matteo; Campello, Silvia; Tam, Wai Leong; Frezza, Christian; Jeyasekharan, Anand D.

doi:10.1038/s41388-022-02219-8

Cited by 5 publications

(8 citation statements)

References 59 publications

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“…Recently, the role of PLK1 in ARID1A-deficient cancer cells has been reported. Cells lacking ARID1A are highly sensitive to PLK1 inhibition [ 90 ]. Interestingly, the sensitivity is related to mitochondrial metabolism rather than to the known role of PLK1 in cell division.…”

Section: Emerging Non-ddr Synthetic Lethal Partnersmentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.

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Section: Emerging Non-ddr Synthetic Lethal Partnersmentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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“…Despite their critical importance in cancer initiation and progression, targeting driver TSGs remains highly challenging as most TSGs are either loss-of-function and exhibit either reduced or silenced expression in cancer cells. There is thus strong interest in targeting molecular pathways either required or activated as a consequence of TSG loss, a concept sometimes termed as ‘synthetic lethality’ 47. Identifying synthetic lethal strategies for TSGs require a precise understanding of the functional pathways regulated by the TSG.…”

Section: Discussionmentioning

confidence: 99%

“…Examples include the targeting of BRCA1 / 2 -deficient cancers by PARP inhibitors exploiting defects in DNA damage repair,48 and WRN helicase inhibitors in MSI cancers 49. For ARID1A , several studies have proposed therapeutic approaches for ARID1A -deficient cells, such as PLK1 or PARP inhibition,15 50 GSH inhibition targeting vulnerabilities in glutathione metabolism,19 ATR inhibition targeting cell cycle defects51 and mTOR inhibition 52. However, ARID1A, as a member of the SWI/SNF chromatin complex, may have multiple functions as chromatin regulatory pathways are often highly dependent on tissue and lineage state 53.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular phenotyping ofARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities

Huang

Law

et al. 2023

Gut

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ObjectiveGastric cancer (GC) is a leading cause of cancer mortality, withARID1Abeing the second most frequently mutated driver gene in GC. We sought to decipherARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising fromARID1Aloss.DesignGenomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures ofARID1Ainactivation across molecular subtypes. Single-cell transcriptomic profiles ofARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising fromARID1Aloss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks ofARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition.ResultsWe observed prevalentARID1Ainactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment.ARID1A-depletion caused loss of H3K27ac activation signals atARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such asNFKB1andNFKB2. Promoter activation inARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific toARID1A-genomic status.ConclusionOur results suggest a therapeutic strategy forARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.

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“…Finally, recent studies have implicated mitochondrial and metabolic reprogramming as new vulnerabilities of ARID1A deficiency. Srinivas et al demonstrated that cells lacking ARID1A are highly sensitive to inhibition of polo-like kinase 1 (PLK1) [ 58 ]. PLK1, a serine-threonine kinase, plays a critical role in cell cycle progression, cell division and DNA damage response and overexpression of PLK1 promotes cell proliferation [ 59 ].…”

Section: Arid1a-deficiency: An Immune-metabolic Vulnerabilitymentioning

confidence: 99%

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

Lebedev

Kousar

Patrick

et al. 2023

Cells

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Epigenetic remodeling and metabolic reprogramming, two well-known cancer hallmarks, are highly intertwined. In addition to their abilities to confer cancer cell growth advantage, these alterations play a critical role in dynamically shaping the tumor microenvironment and antitumor immunity. Recent studies point toward the interplay between epigenetic regulation and metabolic rewiring as a potentially targetable Achilles’ heel in cancer. In this review, we explore the key metabolic mechanisms that underpin the immunomodulatory role of AT-rich interaction domain 1A (ARID1A), the most frequently mutated epigenetic regulator across human cancers. We will summarize the recent advances in targeting ARID1A-deficient cancers by harnessing immune-metabolic vulnerability elicited by ARID1A deficiency to stimulate antitumor immune response, and ultimately, to improve patient outcome.

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PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Cited by 5 publications

References 59 publications

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Comprehensive molecular phenotyping ofARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

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