Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

Wittig-Blaich, Stephanie; Wittig, Rainer; Schmidt, Steffen; Lyer, Stefan; Bewerunge-Hudler, Melanie; Gronert-Sum, Sabine; Strobel-Freidekind, Olga; Müller, Carolin; List, Markus; jaskot, Aleksandra; Christiansen, Helle; Hafner, Mathias; Schadendorf, Dirk; Block, Ines; Mollenhauer, Jan

doi:10.18632/oncotarget.15863

Cited by 19 publications

(19 citation statements)

References 45 publications

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“…In BRAF V600E melanoma, elevated expression of DUSP6 levels is required to compensate for BRAF V600E hyperactivation, which might otherwise trigger apoptosis via ERK1/2 downstream targets. This finding using BRAF V600E melanoma highlights the oncogenic role of DUSP6 via ERK1/2-mediated phosphorylation, and it successfully proves the concept that tumor suppressor DUSP6 could serve as a putative synthetic lethal target in melanoma with BRAF V600E mutations 116 .…”

Section: Dusp6supporting

confidence: 55%

“…Further analysis showed consistent elevated levels of only DUSP6 mRNA expression in primary melanoma and melanoma cell lines compared to primary normal human epidermal melanocytes (NHEMs). The mRNA expression of the other four genes was not consistently elevated in primary melanoma and melanoma cell lines compared to NHEMs 116 . Analysis using siRNA-mediated knockdown of DUSP6 in BRAF wild-type melanoma resulted in either promotion of cell growth or no effect.…”

Section: Dusp6mentioning

confidence: 76%

“…Analysis using siRNA-mediated knockdown of DUSP6 in BRAF wild-type melanoma resulted in either promotion of cell growth or no effect. However, knockdown of DUSP6 in BRAF V600E melanoma with high DUSP6 expression caused cell death via induction of apoptosis, which further illustrates the tumor-suppressive role of DUSP6 116 . BRAF V600E has been implicated in melanoma progression in several different mechanisms, such as by activation of the downstream MEK/ERK pathway, angiogenesis, evasion of senescence, and apoptosis 117 .…”

Section: Dusp6mentioning

confidence: 88%

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Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Ahmad

Abdollah

Shafie

et al. 2018

Cancer Biology & Medicine

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Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.

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Section: Dusp6supporting

confidence: 55%

Section: Dusp6mentioning

confidence: 76%

Section: Dusp6mentioning

confidence: 88%

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Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Ahmad

Abdollah

Shafie

et al. 2018

Cancer Biology & Medicine

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“…However, the DUSP6 V114L variant has been recently associated with an increased risk of lung squamous carcinoma and advanced stages of non‐small cell lung cancer . DUSP6 has been reported as a putative therapeutic target in BRAF V600E /DUSP6 high melanoma cells as DUSP6 inhibition could promote ERK1/2‐mediated hyperactivation of RPS6KA2 followed by apoptosis induction . Further studies are needed to verify how different DUSP6 expression in the context of lack of damaging mutations in RPS6KA2 can be exploited from the potential therapeutic point of view.…”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitindependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF V600E ) and RAS subtypes, including NRAS Q61R and the rare HRAS Q61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RAS Q61R cell lines harbored a MEK1 P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRAS Q61R /MEK P124S cells by trametinib, and this effect was also shown in HRAS Q61R / MEK P124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2 S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2 F1209V and NOTCH2 N2002S variants. Additionally, we found a novel FBXW7 V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas.

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“…Previous studies of gene-expression profiling and proteomics, next-generation sequencing, genomic mutations, methylation status, chromosomal amplification and loss of heterozygosity (LOH) are discussed in the context of CCC biology (18)(19)(20)(21). Furthermore, investigators have developed a new method to predict the synthetic lethality interactions: Synthetic lethality gene pairs may be predicted in functional genomic screening approaches such as CRISPR and siRNA in cancer cells treated with or without PARP inhibitors (22,23).…”

Section: Future Opportunities In the Use Of Parp Inhibition In CCCmentioning

confidence: 99%

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Abstract. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.

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Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

Cited by 19 publications

References 45 publications

Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

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