SMARCA4 biology in alveolar rhabdomyosarcoma

Bharathy, Narendra; Cleary, Megan M.; Kim, Jinah; Nagamori, Kiyo; Crawford, Kenneth A.; Wang, Eric; Saha, Debarya; Settelmeyer, Teagan P.; Purohit, Reshma; Skopelitis, Damianos S.; Chang, Kenneth; Doran, Jessica A; Kirschbaum, C. Ward; Bharathy, Suriya; Crews, Davis W; Randolph, Matthew; Karnezis, Anthony N.; Hudson-Price, Lisa; Dhawan, Jyotsna; Michalek, Joel E.; Ciulli, Alessio; Vakoc, Christopher R.; Keller, Charles

doi:10.1038/s41388-022-02205-0

Cited by 9 publications

(8 citation statements)

References 36 publications

(42 reference statements)

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“…In contrast to the non-degrader form of ACBI1, which had no anti-cancer effect, the ACBI1 PROTAC killed SMARCA4-dependent leukemia cells as well as SWI/SNF-deficient cancer cells that are dependent on residual SWI/SNF activity. ACBI1 also compromised the growth of alveolar rhabdomyosarcoma tumors harboring the PAX3:FOX01 oncogene, demonstrating its anti-cancer effects in vivo [170].…”

Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 93%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

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Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 93%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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“…Moreover, the SWI/SNF complex and the PRC2 complex containing EZH2 methyltransferase have been shown antagonistic activity in gene transcription ( 104 , 105 ), of which EZH2 has an obvious anti-tumor effect on cell lines and xenografts with concurrent loss of SMARCA2 and SMARCA4 ( 106 , 107 ). Dual loss of SMARCA4 and SMARCA2 also impacts tumor cell growth in PAX3:FOXO1+ARMS ( 108 ).…”

Section: Genetic Combination and Mechanism Of Paralog-based Slmentioning

confidence: 99%

Paralog-based synthetic lethality: rationales and applications

Xin¹,

Zhang²

2023

Front. Oncol.

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Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell’s survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors that exclusively target a single but not both paralogs hinder further clinical development. Here, we review the potential mechanisms of paralog-based SL given their function and genetic combination, and discuss the challenge and application prospects of paralog-based SL in cancer therapeutic discovery.

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“…However, other strategies have been explored, including the targeting of pathways associated with PAX::FOXO1 stability or expression, targeting its transcriptional co-activators or targeting down-stream signaling pathways as previously reviewed [4,5]. Genome-scale CRISPR/Cas9 targeting of epigenetic genes and subsequent validation studies revealed the wild type ATP-dependent chromatin remodeling enzyme SMARCA4 as a crucial vulnerability for the survival of both human fusion-positive alveolar and fusion-negative embryonal rhabdomyosarcoma cells [129,131,132]. SMARCA4 and its paralogue SMARCA2 act as catalytic ATPase subunits of the SWI/SNF complexes, including BAF, PBAF and ncBAF, representing fundamental epigenetic regulators of gene transcription [133].…”

Section: Enhancing Target Selectivity To Smarca4/a2 In Rhabdomyosarcomamentioning

confidence: 99%

“…SMARCA4 and its paralogue SMARCA2 act as catalytic ATPase subunits of the SWI/SNF complexes, including BAF, PBAF and ncBAF, representing fundamental epigenetic regulators of gene transcription [133]. In both fusion-positive and fusion-negative cells, in vitro experiments using siRNA, shRNA, or CRISPR-mediated sgRNA SMARCA4 knockdown approaches showed that SMARCA4 loss reduces cell proliferation, anchorage-dependent clonogenicity, and activates myogenic differentiation [129,131,132]. Mechanistically, in fusion-positive cells, SMARCA4 shares a spatial proximity with PAX3::FOXO1 on chromatin even if PAX3::FOXO1 is not incorporated into stable SWI/SNF complexes [129].…”

Section: Enhancing Target Selectivity To Smarca4/a2 In Rhabdomyosarcomamentioning

confidence: 99%

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

Mancarella,

Morrione,

Scotlandi

2023

IJMS

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Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.

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SMARCA4 biology in alveolar rhabdomyosarcoma

Cited by 9 publications

References 36 publications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Paralog-based synthetic lethality: rationales and applications

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

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