The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across ...226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo- and radioresistance. Yet to date, FDA-approved drugs targeting NRF2 activity in cancer have not been realized. Here, we review various mechanisms that contribute to NRF2 activation in cancer, organized around the central dogma of molecular biology (i) at the DNA level with genomic and epigenetic alterations, (ii) at the RNA level including differential mRNA splicing and stability, and (iii) at the protein level comprising altered posttranslational modifications and protein-protein interactions. Ultimately, defining and understanding the mechanisms responsible for NRF2 activation in cancer may lead to novel targets for therapeutic intervention.
SWI/SNF chromatin remodeling complexes and cancer Biegel, Jaclyn A.; Busse, Tracy M.; Weissman, Bernard E.
American journal of medical genetics. Part C, Seminars in medical genetics,
September 2014, Volume:
166C, Issue:
3
Journal Article
Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were ...underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional activity in head and neck squamous carcinomas (HNSC). Many additional tumor types showed significant association between NRF2 signaling and mutation of specific components of the SWI/SNF complex. Different effects of BAF and PBAF mutations on the polarity of NRF2 signaling were observed. Overall, our results support a context-dependent functional link between SWI/SNF and NRF2 mutations across human cancers and implicate ARID1A inactivation in HPV-negative HNSC in promoting tumor progression and survival through activation of the KEAP1-NRF2 signaling pathway. The tumor-specific effects of these mutations open a new area of study for how mutations in the KEAP1-NRF2 pathway and the SWI/SNF complex contribute to cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic ...variants in
, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and ...SMARCA2. A great need exists for effective targeted therapies for SCCOHT.
To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.
The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.
Ponatinib is an effective agent for
-mutant SCCOHT in both
and
preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.
.
SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to ...depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.
Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the ...SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SWI/SNF chromatin remodeling complexes regulate critical cellular processes, including cell-cycle control, programmed cell death, differentiation, genomic instability, and DNA repair. Inactivation of ...this class of chromatin remodeling complex has been associated with a variety of malignancies, including lung, ovarian, renal, liver, and pediatric cancers. In particular, approximately 10% of primary human lung non-small cell lung cancers (NSCLC) display attenuations in the BRG1 ATPase, a core factor in SWI/SNF complexes. To evaluate the role of BRG1 attenuation in NSCLC development, we examined the effect of BRG1 silencing in primary and established human NSCLC cells. BRG1 loss altered cellular morphology and increased tumorigenic potential. Gene expression analyses showed reduced expression of genes known to be associated with progression of human NSCLC. We demonstrated that BRG1 losses in NSCLC cells were associated with variations in chromatin structure, including differences in nucleosome positioning and occupancy surrounding transcriptional start sites of disease-relevant genes. Our results offer direct evidence that BRG1 attenuation contributes to NSCLC aggressiveness by altering nucleosome positioning at a wide range of genes, including key cancer-associated genes.
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