Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition

Abstract

Recent data has identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that STAG2 mutation is associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme poly ADP-ribose polymerase (PARP). STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei and chromatin bridges compared to wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells suggesting that these cells have defects in DNA repair. Furthermore, cells with STAG2 mutations were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA damaging agents. These data suggest that PARP is a potential target for tumours harbouring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.

Genetic alterations of the cohesin complex genes in myeloid malignancies

“…The use of high-throughput next-generation sequencing for somatic mutational profiling has led to the identification of recurrent somatic mutations within the cohesin complex in patients with acute myeloid leukemia (AML), 1,2 myelodysplastic syndrome (MDS), 3 glioblastoma multiforme, 4 Ewing sarcoma, 5 and colorectal 6 and bladder carcinomas. 7,8 Cohesin is a multiprotein complex that has an established role as an effector of sister-chromatid cohesin during metaphase.…”

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

“…Genome sequencing of human cancers has revealed few recurrent mutations in genes responsible for mitosis, with the exception of members of the cohesin complex (Barbero, 2011;Kon et al, 2013;Mannini and Musio, 2011;Thol et al, 2013;Bailey et al, 2013;The Cancer Genome Atlas Research Network, 2014). The vertebrate cohesin core complex is composed of two structural maintenance of chromosome proteins (SMC1 and SMC3), the kleisin subunit Scc1/RAD21 and a stromal antigen protein (STAG).…”

“…Somatically acquired mutations in CIN cancers have been identified in genes encoding SMC1, SMC3 and other cohesinrelated proteins (Barber et al, 2008;Barbero, 2011;Yan et al, 2012). Recently, mutations causing loss of expression of the cohesin subunit STAG2 (also known as SA2) have been identified in numerous cancers (Solomon et al, 2011;Kim et al, 2012;Bernardes et al, 2013;Bailey et al, 2013). Microarray analysis has shown that STAG2 deficiency does not significantly alter gene expression (Solomon et al, 2011).…”

Parp Inhibitors: The Journey from Research Hypothesis to Clinical Approval

“…However, DDR genes other than core HR genes are also biomarkers for increased cytotoxic response to PARP inhibitors, for example, ATM, CHEK2, ERCC1, CDK12 and γ-H2AX [19,[61][62][63][64][65][66][67][68][69]. Other single-gene biomarkers not directly involved in DDR include PTEN, which shows defects in a large fraction of prostate cancers, and STAG2 a component of the cohesin complex [70,71]. This specific approach of identifying and validating single-gene biomarkers for PARP inhibitor sensitivity is ongoing and also high-throughput systems are being developed to systematically and effectively identify these markers [64,72].…”