Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA393349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5809396_1.fastq.gz | Fastqsanger.gz | |||
| SRR5809396_2.fastq.gz | Fastqsanger.gz | |||
| SRR5809397_1.fastq.gz | Fastqsanger.gz | |||
| SRR5809397_2.fastq.gz | Fastqsanger.gz |
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Project description:Activation of TRK family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor with low nanomolar potency against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies. In acute myeloid leukemia (AML) cell lines with endogenous expression of the ETV6-NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein, as well as phosphorylation of known TRKC downstream signaling effectors, was inhibited by entrectinib treatment in a dose-dependent manner. Sensitivity to entrectinib was dependent on expression of the ETV6-TRKC fusion protein. In xenograft models, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion-driven AML and provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.
2018-07-05 | GSE100885 | GEO
Project description:TrkB with its ligand, brain-derived neurotrophic factor (BDNF), are overexpressed in the majority of high-risk neuroblastomas (NBs). Entrectinib is a novel pan-TRK, ALK, and ROS1 inhibitor that has shown excellent preclinical efficacy in NB xenograft models, and recently it has entered phase 1 trials in pediatric relapsed/refractory solid tumors. We examined entrectinib-resistant NB cell lines to identify mechanisms of resistance. Entrectinib-resistant cell lines were established from five NB xenografts initially sensitive to entrectinib therapy. Clonal cell lines were established in increasing concentrations of entrectinib and had >10X increase in IC50. Cell lines underwent genomic and proteomic analysis using whole-exome sequencing, RNA-Seq, and proteomic expression profiling with confirmatory RT-PCR and Western blot analysis. There was no evidence of NTRK2 (TrkB) gene mutation in any resistant cell lines. Inhibition of TrkB was maintained in all cell lines at increasing concentrations of entrectinib (target independent). PTEN pathway downregulation and ERK/MAPK pathway upregulation were demonstrated in all resistant cell lines. One of these clones also had increased IGF1R signaling, and two additional clones had increased P75 expression, which likely increased TrkB sensitivity to ligand. In conclusion, NB lines overexpressing TrkB developed resistance to entrectinib by multiple mechanisms, including activation of ERK/MAPK and downregulation of PTEN signaling. Individual cell lines also had IGF1R activation and increased P75 expression, allowing preservation of downstream TrkB signaling in the presence of entrectinib. An understanding of changes in patterns of expression can be used to inform multimodal therapy planning in using entrectinib in phase II/III trial planning.
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Project description:Utilizing primary, patient tumor-derived ROS1+ NSCLC cell lines, we derived TKI-resistant cell lines by chronic exposure to TKI in the media. One of our parental, ROS1 TKI-sensitive cell lines harbors a TPM3-ROS1 fusion (CUTO28) and the other harbors a CD74-ROS1 fusion (CUTO37). Entrectinib-resistant (-ER) and crizotinib-resistant (-CR) lines are so named when they are stably proliferating at 500nM concentration of the respective TKI. We sought to investigate transcriptome changes with acquired resistance to entrectinib or crizotinib.
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Project description:ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.
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