Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

Sanjiv, Kumar; Hagenkort, Anna; Calderón-Montaño, José Manuel; Koolmeister, Tobias; Reaper, Philip M.; Mortusewicz, Oliver; Jacques, Sylvain; Kuiper, Raoul V.; Schultz, Niklas; Scobie, Martin; Charlton, Peter; Pollard, John R.; Berglund, Ulrika Warpman; Altun, Mikael; Helleday, Thomas

doi:10.1016/j.celrep.2015.12.032

Cited by 121 publications

(102 citation statements)

References 53 publications

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“…CCC have been assumed to demonstrate an increased reliance on the HNF-1β-CHEK1 axis for cell survival (49). Significant genes involved in synthetic lethality with CHEK1 are reported to be ATR, MYC, TP53, WEE1 and CDKN1A (29,(61)(62)(63). ATR inhibition is currently assessed in early-phase clinical trials as single agents and in combination strategies, including PARP inhibitors (37).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitors of ATM may be a promising strategy for cancer therapy (38). ATR and CHEK1 are synthetic lethal pairs between two proteins in the same pathway and maintain cancer cell survival under replication stress (10,29). CCC have been assumed to demonstrate an increased reliance on the HNF-1β-CHEK1 axis for cell survival (49).…”

Section: Discussionmentioning

confidence: 99%

“…These analyses revealed a significant representation in the cell cycle regulation and DNA repair pathways (18)(19)(20). Overexpression of HNF-1β (>90%), CHEK1, X-ray repair cross complementing (XRCC) 5, cyclin (CCN) E1 and CDC28 protein kinase regulatory subunit 1B (CKS1B) is a common genetic change in CCC (28,29,(47)(48)(49). A novel role for transcription factor HNF-1β in DDR was identified (49).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratiomentioning

confidence: 99%

“…The genetic mutations related to chromatin remodeling, DNA repair signaling, PI3K-AKT-mTOR, Notch signaling and CTNNB1 pathway may be involved in CCC biology (27). The frequently mutated genes were PIK3CA (60%), ARID1A (50%) and PTEN (10%) in CCC (27)(28)(29)(30)(31). Somatic mutations of these genes are common genetic changes.…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratiomentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratiomentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratiomentioning

confidence: 99%

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

et al. 2017

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“…The ATR and Chk1 kinases, critical mediators of the DNA damage response pathway, maintain cell survival and protect cells from replication stress (46). These two kinases are currently the focus of ongoing clinical trials (47). Inhibition of Raf-1 proto-oncogene serine threonine kinase (RAF1) is a synthetic lethal target in KRAS mutant tumor types (48).…”

Section: Categorymentioning

confidence: 99%

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

et al. 2018

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Abstract. Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

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Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up‐regulation

et al. 2021

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Platinum‐based chemotherapy has been the cornerstone treatment for small cell lung cancer (SCLC) for decades, but no major progress has been made in the past 20 years with regard to overcoming chemoresistance. As the cell cycle checkpoint kinase 1 (Chk1) plays a key role in DNA damage response to chemotherapeutic drugs, we explored the mechanisms of acquired drug resistance to the Chk1 inhibitor prexasertib in SCLC. We established prexasertib resistance in two SCLC cell lines and found that DNA copy number, messengerRNA (mRNA) and protein levels of the cell cycle regulator Wee1 significantly correlate with the level of acquired resistance. Wee1 small interfering RNA (siRNA) or Wee1 inhibitor reversed prexasertib resistance, whereas Wee1 transfection induced prexasertib resistance in parental cells. Reverse phase protein microarray identified up‐regulated proteins in the resistant cell lines that are involved in apoptosis, cell proliferation and cell cycle. Down‐regulation of CDK1 and CDC25C kinases promoted acquired resistance in parental cells, whereas down‐regulation of p38MAPK reversed the resistance. High Wee1 expression was significantly correlated with better prognosis of resected SCLC patients. Our results indicate that Wee1 overexpression plays an important role in acquired resistance to Chk1 inhibition. We also show that bypass activation of the p38MAPK signaling pathway may contribute to acquired resistance to Chk1 inhibition. The combination of Chk1 and Wee1 inhibitors may provide a new therapeutic strategy for the treatment of SCLC.

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Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

Cited by 121 publications

References 53 publications

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

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

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up‐regulation

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