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| Ref Type | Journal Article | ||||||||||||
| PMID | (25686104) | ||||||||||||
| Authors | Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih IeM, Conejo-Garcia JR, Speicher DW, Zhang R | ||||||||||||
| Title | Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. | ||||||||||||
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| Abstract Text | The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations. | ||||||||||||
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| GSK126 | GSK2816126|GSK-126 | EZH2 inhibitor 20 | GSK126 selectively inhibits EZH2, resulting in decreased H3K27 tri-methylation, and potentially leading to decreased tumor cell proliferation and reduced tumor growth (PMID: 23051747, PMID: 25686104, PMID: 31471312). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ARID1A mutant | ovarian cancer | sensitive | GSK126 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, GSK126 selectively inhibited growth of ARID1A-mutant ovarian cancer cells in culture, and induced tumor regression in ARID1A-mutant ovarian cancer xenograft models (PMID: 25686104). | 25686104 |
| ARID1A dec exp | ovarian cancer | sensitive | GSK126 | Preclinical - Cell culture | Actionable | In a preclinical study, GSK126 inhibited growth of ovarian cancer cells with knockdown of ARID1A expression in culture (PMID: 25686104). | 25686104 |
| ARID1A mut PIK3CA act mut | ovarian cancer | sensitive | GSK126 | Preclinical - Cell culture | Actionable | In a preclinical study, expression of a constitutively active PIK3CA mutation in ARID1A-mutant ovarian cancer cell lines enhanced growth inhibition by GSK126 in culture (PMID: 25686104). | 25686104 |
| ARID1A mutant | ovarian cancer | sensitive | UNC1999 | Preclinical - Cell culture | Actionable | In a preclinical study, UNC1999 inhibited growth of ovarian cancer cell lines harboring ARID1A mutations in culture (PMID: 25686104). | 25686104 |
| ARID1A wild-type | ovarian cancer | no benefit | GSK126 | Preclinical - Cell culture | Actionable | In a preclinical study, GSK126 had no significant effect on the growth of ovarian cancer cells with wild-type ARID1A in culture (PMID: 25686104). | 25686104 |