Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence

Ou, Wen‐Bin; Ni, Nan; Zuo, Rui; Zhuang, Wenhua; Zhu, Mei‐Jun; Kyriazoglou, Anastasios; Wu, Duolin; Eilers, Grant; Demetri, George D.; Qiu, Haibo; Li, Bin; Mariño-Enríquez, Adrián; Fletcher, Jonathan A.

doi:10.1038/s41388-019-0894-3

Cited by 24 publications

(24 citation statements)

References 51 publications

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Section: Mk-1775 and Avapritinib Have Enhanced Combination Effects Onsupporting

confidence: 88%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

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Gastrointestinal stromal tumor (GIST) management has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of receptor tyrosine kinase (RTK) inhibitors in advanced disease. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GIST, resistance remains a significant clinical obstacle.Development of effective strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes.PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a monotherapy in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Section: Mk-1775 and Avapritinib Have Enhanced Combination Effects Onsupporting

confidence: 88%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

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“…We hypothesize that this increased DNA damage may be a result of loss of cell cycle checkpoints and decreased time for DNA repair mechanisms ultimately causing increased cell death. Interestingly, the KIT-independent cell line, GIST-T1+D842V KIT KO , has significantly more cyclin D1 than the KIT-dependent line, GIST-T1+Cas9, in accordance with a recent report(37), providing a potential explanation for the differential effects of MK-1775 and avapritinib in these two cell lines.Combination treatment reduces tumor growth and improves survival in vivoOn the basis of these strong in vitro data, we hypothesized that there would be benefit insimultaneously inhibiting KIT/PDGFRA and Wee1 leading to loss of cell cycle checkpoint arrest, increased DNA damage and ultimately increased cell death. To test this hypothesis, we performed a GIST xenograft study under a FCCC Institutional Animal Care protocol using the GIST-T1+Cas9 and GIST-T1+D842V KIT KO cell lines.…”

supporting

confidence: 88%

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Ye¹,

Sharipova²,

Kozinova³

et al. 2021

JCI Insight

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Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes ( KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G 2 /M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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“…However, the role of the Hippo signaling pathway in the pathogenesis of GIST has not been well studied. Qu et al found that the hippo pathway effectors YAP and TAZ could coordinately regulate cyclin D1 expression, which functions as an oncogenic mediator in KIT-independent GISTs [33]. Our study indicated that the Hippo signaling pathway was the most relevant pathway regulated by lncRNAs involved in the proliferation and mitosis of GISTs, suggesting that the Hippo signaling pathway may play a crucial role in lncRNAmediated regulation of malignant transformation of GISTs.…”

Section: Discussionsupporting

confidence: 53%

Integrated Analysis of Long Non-Coding RNAs and mRNAs Associated With Malignant Transformation of Gastrointestinal Stromal Tumors

Yin

Dai

et al. 2020

Preprint

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Abstract Background: Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. Methods: In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients’ prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Results: Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Conclusions: These results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.

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Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence

Cited by 24 publications

References 51 publications

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Integrated Analysis of Long Non-Coding RNAs and mRNAs Associated With Malignant Transformation of Gastrointestinal Stromal Tumors

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