Ontology highlight
ABSTRACT:
PROVIDER: PRJNA848127 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21994802_1.fastq.gz | Fastqsanger.gz | |||
| SRR21994802_2.fastq.gz | Fastqsanger.gz | |||
| SRR21994803_1.fastq.gz | Fastqsanger.gz | |||
| SRR21994803_2.fastq.gz | Fastqsanger.gz | |||
| SRR21994804_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteosarcoma is a prevalent primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors emerged as potential treatment for osteosarcoma due to the critical role of kinases regulating network. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a systematic combination screening of kinase inhibitors was further conducted in osteosarcoma cells. Among 190 pair-wise combinations, 44 exhibited strong synergistic antitumor efficacy. Notably, the combination of the ALK inhibitor Ceritinib and the FLT3 inhibitor Crenolanib showed significant synergistic effects against osteosarcoma cell lines, patient-derived organoids in vitro, and xenograft models in vivo. This combination also effectively mitigated the compensatory activation of oncogenic signaling pathways, a common resistance mechanism to single-agent therapies. Our findings provide compelling evidence that dual kinase inhibition targeting ALK and FLT3 can effectively exploit pharmacological vulnerabilities in osteosarcoma, suggesting a promising therapeutic strategy for clinical application. This combinatorial approach could potentially overcome the limitations of single-agent therapies and improve outcomes for patients with osteosarcoma. Further clinical evaluation is warranted to confirm these preclinical results.
2024-10-29 | GSE278302 | GEO
Project description:Linking clinical multi-omics analyses with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in truncated ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for CDK4/6- and PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling indicate a close relationship with undifferentiated sarcomas. Finally, in two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, providing insight into stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.
2023-11-06 | GSE224183 | GEO
Project description:Linking clinical multi-omics analyses with mechanistic studies may improve the understanding of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibited outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing. This resulted in the expression of ALK variants, i.e. short transcripts (ST), which we named ALK-ST1 (consisting of exons 1-2:18–29), ALK-ST2 (1:18–29), ALK-ST3 (18–29), and ALK-ST4 (1–5:12–17). To systematically investigate the oncogenic capacity of these ALK variants, we stably expressed them in p53-deficient MCF10A human mammary epithelial cells and performed different transformation assays. These experiments demonstrated that ALK-ST1, ALK-ST2, and ALK-ST3 are oncogenic variants, while ALK-ST4 could not transform MCF10A cells. We confirmed protein expression of ALK-ST1, ALK-ST2, and ALK-ST3 by western blotting, which was not possible for ALK-ST4 due to lack of a specific antibody that binds to the N-terminus of ALK that is lost in ALK-ST4. We therefore performed mass spectrometry-based label-free quantitative proteomics on lysates from MCF10A cells stably expressing empty vector (EV), wildtype ALK (ALK-WT), or ALK-ST4 to confirm its expression.
2023-11-13 | PXD045522 | Pride
Project description:Despite the initial benefit of the tyrosine kinase inhibitors targeting ALK gene fusions in non-small cell lung cancer, resistance to ALK inhibitors is almost inevitable. To determine the acquired resistance mechanism to ALK inhibition, we generated crizotinib-resistant ALK lines by chronically treating H3122 cells (driven by EML4-ALK) with an ALK inhibitor, crizotinib for approximately 3 months. RNA-seq and differential expression analyses were performed to determine the transcriptional changes of H3122-CR cells in comparison to parental H3122 cells. Because we demonstrated EGFR could mediate the early adaptive resistance to crizotinib, we further explored the mechanism that contributes to the resistance to the combination of crizotinib and afatinib. H3122-CAR (crizotinib and afatinib-resistant) cells were generated by treating them with a combination of crizotinib and afatinib for approximately 6 months and then profiled by RNA-seq to determine the associated transcriptional reprogramming.
2023-07-31 | GSE239666 | GEO
Project description:Identification of genes up-regulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. To elucidate molecular characteristics of lung adenocarcinomas (ADCs) with ALK mutations and those without EGFR, KRAS and ALK mutations, 226 primary lung ADCs of pathological stage I-II, examined for the status of EGFR, KRAS and ALK mutations, were subjected to genome-wide expression profiling, and genes up-regulated in lung ADCs with ALK mutations and those without EGFR, KRAS and ALK mutations were identified. One hundred and seventy-four genes, including ALK, were selected as being up-regulated specifically in 79 lung ADCs without EGFR and KRAS mutations. These 79 cases were divided into: 11 cases of ALK-positive ADCs, 36 cases of group A triple-negative ADCs, and 32 cases of group B triple-negative ADCs, by unsupervised clustering according to the expression of the 174 genes. In ALK-positive ADCs, 30 genes, including ALK itself and GRIN2A, were significantly overexpressed. Group A triple-negative ADC cases showed significantly worse prognoses for relapse and death than ADC cases with EGFR, KRAS or ALK mutations and group B triple-negative ADC cases. Nine genes were identified as being significantly up-regulated in group A triple-negative ADC cases and critical for predicting their prognosis. The nine genes included DEPDC1, which had been identified as a candidate diagnostic and therapeutic target in bladder and breast cancers. Genes discriminating this group of ADCs will be useful for selection of patients who will benefit from adjuvant chemotherapy after surgical resection of stage I-II triple-negative ADCs and also informative for the development of molecular targeting therapies for these patients. Expression profiles in of 226 lung adenocarcinomas (127 with EGFR mutation, 20 with KRAS mutation, 11 with EML4-ALK fusion and 68 triple negative cases).
2011-11-01 | E-GEOD-31210 | biostudies-arrayexpress
Project description:Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.
2024-04-11 | PXD042728 | Pride
Project description:Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.
2024-04-11 | PXD043012 | Pride
Project description:Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. A previous study identified the Anaplastic Lymphoma Kinase (ALK) amplification in HCC patients, raising the question of whether ALK inhibitors could be a viable treatment. Here, we showed that both ALK inhibitors and ALK knockout effectively halted HCC growth in cell cultures. Lorlatinib, a potent ALK inhibitor, suppressed HCC tumor growth and metastasis across various mouse models. Additionally, in an advanced immunocompetent humanized mouse model, when combined with an anti-PD-1 antibody, lorlatinib more potently suppressed HCC tumor growth, surpassing individual drug efficacy. Lorlatinib induced apoptosis and senescence in HCC cells, and the senolytic agent ABT-263 enhanced the efficacy of lorlatinib. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.
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Project description:The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3-6μM PCI-34051 or 10μM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05μM (ALK-amplified) to 0.8μM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n=88) and the German Neuroblastoma Trial cohort (n=649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.
2018-02-21 | GSE110817 | GEO
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