Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical

Kong, Yichao; Jiang, Caihong; Wei, Guifeng; Kim, Sun; Wang, Ruijie; Qiu, Ting

doi:10.3390/molecules28124672

Cited by 4 publications

(4 citation statements)

References 273 publications

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“…Advancing our understanding of the dynamic nature and constituent elements of the signal niche, as well as its communication with downstream targets, will provide valuable insights into the molecular mechanisms governing the aberrant Ras/MAPK signaling cascade driven by the CCDC6-RET fusion. Furthermore, we found that a significant proportion of RET fusion proteins, including KIF5B-RET and NCOA4-RET, possess the coiled-coil domain within their fusion partners ( 72 – 74 ). This observation raises the intriguing possibility that RET fusion proteins may recruit signaling proteins via LLPS, thereby contributing to the promotion of cancers.…”

Section: Discussionmentioning

confidence: 93%

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche

Qiu,

Kong,

Wei

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid–liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion–related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion–driven diseases.

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Section: Discussionmentioning

confidence: 93%

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche

Qiu,

Kong,

Wei

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…Evidence suggests that BCR-ABL proteins are present in granule-like structures in myeloid and lymphoid cells 53 , 54 . These BCR-ABL proteins are predicted to possess long IDRs, which endow weak multivalency and potentially facilitate phase separation and granule formation 55 , 56 . Kashiwagi et al revealed that BCR-ABL-positive granules were SGs 57 .…”

Section: Llps In Leukemia and Myelomamentioning

confidence: 99%

Liquid‒liquid phase separation: roles and implications in future cancer treatment

Liu¹,

Qin²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Liquid‒liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation of distinct liquid-like condensates. Through LLPS, membraneless condensates are formed, selectively concentrating specific proteins while excluding other molecules to maintain normal cellular functions. Emerging evidence shows that cancer-related mutations cause aberrant condensate assembly, resulting in disrupted signal transduction, impaired DNA repair, and abnormal chromatin organization and eventually contributing to tumorigenesis. The objective of this review is to summarize recent advancements in understanding the potential implications of LLPS in the contexts of cancer progression and therapeutic interventions. By interfering with LLPS, it may be possible to restore normal cellular processes and inhibit tumor progression. The underlying mechanisms and potential drug targets associated with LLPS in cancer are discussed, shedding light on promising opportunities for novel therapeutic interventions.

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“…In recent years, oncogenic fusion genes have been identified in various cancer types because of the recent undertaking of extensive genomic analyses of clinical samples [ 1 , 2 , 3 ]. These oncogenic fusions may serve as potential therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

“…These oncogenic fusions may serve as potential therapeutic targets. In particular, fusion genes comprising the kinase domains of druggable receptor tyrosine kinases (RTKs), such as epidermal growth factor receptors or anaplastic lymphoma kinases, are used clinically as favorable therapeutic targets against malignancies [ 2 , 4 , 5 , 6 ]. Therefore, screening for oncogenic fusions is important for the diagnosis and treatment of cancers.…”

Section: Introductionmentioning

confidence: 99%

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway

Fujii,

Nakano,

Hagita

et al. 2023

Cancers

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Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

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Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical

Cited by 4 publications

References 273 publications

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche

Liquid‒liquid phase separation: roles and implications in future cancer treatment

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway

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