Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib

Zhu, Gangjie; Shi, Jun; Zhang, Shaoting; Guo, Yue; Huang, Ling; Zhao, Hui; Jiang, Yideng; Sun, Jianmin

doi:10.1186/s13578-020-0377-9

Cited by 8 publications

(9 citation statements)

References 50 publications

(84 reference statements)

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“…Oncogenic KIT mutations often occur in malignancies such as GISTs and mastocytosis [ 3 , 7 ], and our previous studies suggested that KIT mutants mediated distinct signaling pathways in addition to the ligand-independent activation [ [20] , [21] , [22] ]. In order to know whether PTPRE attenuates the activation of KIT mutants similarly as wild-type KIT, we further studied the function of PTPRE on the activation of KIT mutation D816V which is the most often happened mutation in mastocytosis.…”

Section: Resultsmentioning

confidence: 99%

“…KIT is a receptor tyrosine kinase that plays an important role in hematopoiesis, gametogenesis and melanogensis, and oncogenic KIT mutations have been identified in GISTs, mastocytosis, acute myeloid leukemia, melanoma and others [ [1] , [2] , [3] , 7 , 23 , 24 ]. Signaling studies of wild-type KIT and KIT mutants have showed that KIT mutants have different signaling properties in addition to the ligand independent activation which was considered as the main cause of cell transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Similar as mastocytosis, GISTs are dominated by KIT mutations as well although they harbor different types of KIT mutations. In GISTs, KIT mutations mainly map to exon 11 of KIT, followed by exon 9, 13 and 14 [ [7] , [8] , [9] , [10] , [11] , [12] ]. The reason why mastocytosis and GISTs carry different types of KIT mutations is not well understood yet.…”

Section: Introductionmentioning

confidence: 99%

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Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

Zhang

Jiang

et al. 2021

Biochemistry and Biophysics Reports

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Activation of receptor tyrosine kinases needs tight control by tyrosine phosphatases to keep their normal function. In this study, we investigated the regulation of activation of the type III receptor tyrosine kinase KIT by protein tyrosine phosphatase receptor type E (PTPRE). We found that PTPRE can associate with wild-type KIT and inhibit KIT activation in a dose-dependent manner, although the activation of wild-type KIT is dramatically inhibited even when PTPRE is expressed at low level. The D816V mutation of KIT is the most frequently found oncogenic mutation in mastocytosis, and we found that PTPRE can associate and inhibit the activation of KIT/D816V in a dose dependent manner, but the inhibition is much weaker compared with wild-type KIT. Similar to mastocytosis, KIT mutations are the main oncogenic mutations in gastrointestinal stromal tumors (GISTs) although GISTs carry different types of KIT mutations. We further studied the regulation of the activation of GISTs-type KIT mutants and other mastocytosis-type KIT mutants by PTPRE. Indeed, PTPRE can almost block the activation of GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to the inhibition of PTPRE. Taken together, our results suggest that PTPRE can associate with KIT, and inhibit the activation of both wild-type KIT and GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to PTPRE.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

Zhang

Jiang

et al. 2021

Biochemistry and Biophysics Reports

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“…To produce Ba/F3 cells expressing KIT and either DDR1 or DDR2, EcoPack cells were transfected with either pMSCVneo/DDR1 or pMSCVneo/DDR2 using lipofectamine 2000 in accordance with the manufacturer's instructions. Supernatants were harvested 48 h after transfection and were used to infect Ba/F3 cells expressing either wild‐type KIT or KIT mutants previously established 24 . After selection with 1 mg/mL neomycin for 2 weeks, the expression of DDR1 or DDR2 was examined by western blot analysis.…”

Section: Materials and Medthodsmentioning

confidence: 99%

DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors

Liu,

Zhang,

Wang

et al. 2023

Molecular Carcinogenesis

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Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild‐type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first‐line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild‐type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT‐targeted therapy. The development of drug‐resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.

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“…Gain-of-function mutations of KIT have been identified in around 80% of gastrointestinal stromal tumors (GISTs) (Tarn et al, 2005;Steigen et al, 2007;Zhu et al, 2020) and mastocytosis (Nagata et al, 1995;Longley et al, 1999), and to a lesser extent in acute myeloid leukemia (Boissel et al, 2006) and germ cell tumors (Looijenga et al, 2003). Among all the mutations, D816V mutation in exon 17 of KIT is the most often occurred mutation which accounts for around 70% of mastocytosis but it is rarely found in GISTs.…”

Section: Introductionmentioning

confidence: 99%

PI3 kinase isoform p110δ is more important than p110α in KIT signaling in hematopoietic cells

ZHANG¹,

ZHANG²,

FAN³

et al. 2022

Biocell

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PI3 kinases are important for KIT signaling and KIT mutants mediated cell transformation. In order to know the difference of PI3 kinase isoforms p110α and p110δ in the signaling of wild-type KIT and the often occurred KIT mutation D816V in hematopoietic malignancy mastocytosis, the predominant PI3 kinase isoform p110δ in hematopoietic tissues was knocked out in hematopoietic cells. We found that loss of p110δ expression dramatically inhibits PI3 kinase activation mediated by both wild-type KIT and KIT/D816V. By over expression of p110α in p110δ knock out cells, wild-type KIT mediated PI3 kinase activation was not changed while over expression of p110δ increased PI3 kinase activation.Similarly, in KIT/D816V expressing cells without p110δ expression, over expression of p110δ but not p110α restored PI3 kinase activation. In agreement with the signaling results, cell proliferation, cell survival and cell cycle assay further showed that over expression of p110δ but not p110α in p110δ knock out cells increases both wild-type KIT and KIT/D816V mediated cell survival and proliferation. These results suggested that p110δ plays a more important role than p110α in KIT signaling and KIT mutant mediated cell transformation in hematopoietic cells.

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Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib

Cited by 8 publications

References 50 publications

Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors

PI3 kinase isoform p110δ is more important than p110α in KIT signaling in hematopoietic cells

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