New perspectives for targeting therapy in ALK-positive human cancers

Zhao, Simin; Li, Jian; Xia, Qingxin; Liu, Kangdong; Dong, Zigang

doi:10.1038/s41388-023-02712-8

Cited by 12 publications

(7 citation statements)

References 94 publications

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“…Notably, the abovementioned ALKAL2-ALK signaling [ 50 – 53 ] and PDGFA-PDGFRB signaling [ 54 , 55 ] have been reportedly important in breast cancer growth and metastasis. Moreover, the PI3K-AKT pathway has been validated as the downstream signaling pathways of ALKAL2-ALK signaling and PDGFA-PDGFRB signaling in human cancers [ 53 , 56 , 57 ]. These findings suggest important functional interactions between the 2 regions IDC_4 and Tumor_edge_1 through LR interactions in the tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

Dissecting Spatiotemporal Structures in Spatial Transcriptomics via Diffusion-Based Adversarial Learning

Wang,

Zhao,

Nie

et al. 2024

Research

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Recent advancements in spatial transcriptomics (ST) technologies offer unprecedented opportunities to unveil the spatial heterogeneity of gene expression and cell states within tissues. Despite these capabilities of the ST data, accurately dissecting spatiotemporal structures (e.g., spatial domains, temporal trajectories, and functional interactions) remains challenging. Here, we introduce a computational framework, PearlST ( p artial differential equation [PDE]- e nhanced a dversa r ia l graph autoencoder of ST ), for accurate inference of spatiotemporal structures from the ST data using PDE-enhanced adversarial graph autoencoder. PearlST employs contrastive learning to extract histological image features, integrates a PDE-based diffusion model to enhance characterization of spatial features at domain boundaries, and learns the latent low-dimensional embeddings via Wasserstein adversarial regularized graph autoencoders. Comparative analyses across multiple ST datasets with varying resolutions demonstrate that PearlST outperforms existing methods in spatial clustering, trajectory inference, and pseudotime analysis. Furthermore, PearlST elucidates functional regulations of the latent features by linking intercellular ligand–receptor interactions to most contributing genes of the low-dimensional embeddings, as illustrated in a human breast cancer dataset. Overall, PearlST proves to be a powerful tool for extracting interpretable latent features and dissecting intricate spatiotemporal structures in ST data across various biological contexts.

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Section: Resultsmentioning

confidence: 99%

Dissecting Spatiotemporal Structures in Spatial Transcriptomics via Diffusion-Based Adversarial Learning

Wang,

Zhao,

Nie

et al. 2024

Research

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“…Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that plays a pivotal role in various cellular processes, including cell growth, differentiation, and migration. 7 , 8 , 9 Originally identified as an oncogene in lymphomas, ALK aberrations have been implicated in diverse malignancies, including non-small cell lung cancer (NSCLC) and neuroblastoma. 7 , 8 , 9 , 10 ALK aberrations often lead to constitutive kinase activity and uncontrolled cell proliferation, making them attractive targets for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

“… 7 , 8 , 9 Originally identified as an oncogene in lymphomas, ALK aberrations have been implicated in diverse malignancies, including non-small cell lung cancer (NSCLC) and neuroblastoma. 7 , 8 , 9 , 10 ALK aberrations often lead to constitutive kinase activity and uncontrolled cell proliferation, making them attractive targets for therapeutic intervention. Because of the oncogenic role of ALK in various cancers, patients with ALK-positive tumors are often treated with ALK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the oncogenic role of ALK in various cancers, patients with ALK-positive tumors are often treated with ALK inhibitors. 7 , 8 , 9 Overall, ALK inhibitors have shown superior therapeutic outcomes in ALK-positive lung cancer patients compared to chemotherapy, and third-generation ALK inhibitors such as lorlatinib have shown better survival benefits in ALK-positive lung cancers compared to previous-generation ALK inhibitors such as crizotinib. 11 Similarly, ALK inhibitors have been shown to be efficacious against other ALK-positive cancers.…”

Section: Introductionmentioning

confidence: 99%

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ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models

Bugide,

Reddy,

Malvi

et al. 2024

iScience

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“…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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New perspectives for targeting therapy in ALK-positive human cancers

Cited by 12 publications

References 94 publications

Dissecting Spatiotemporal Structures in Spatial Transcriptomics via Diffusion-Based Adversarial Learning

Dissecting Spatiotemporal Structures in Spatial Transcriptomics via Diffusion-Based Adversarial Learning

ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models

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

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