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Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

ABSTRACT: RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69226 | GEO | 2015/09/01

SECONDARY ACCESSION(S): PRJNA284924

REPOSITORIES: GEO

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Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. To identify potential mechanisms of acquired resistance to dovitinib, we established LC-2/ad DR cells with acquired resistance to dovitinib by exposing LC-2/ad cells to increasing doses of dovitinib. LC-2/ad DR cells showed strong resistance to dovitinib (IC50> 3 μmol/L). Next, LC-2/ad and LC-2/ad DR cells were subjected to genome-wide gene expression profiling using cDNA microarray.

2015-09-01 | E-GEOD-69226 | biostudies-arrayexpress

Sequencing of ponatinib-resistant LC-2/ad derivatives (PR1 and PR2) and parental LC-2/ad cells

Project description:Sequencing of ponatinib-resistant LC-2/ad derivatives (PR1 and PR2) and parental LC-2/ad cells was performed in order to determine mechanisms of acquired resistance in the PR1 and PR2 cell lines. NRAS p.Q61K mutation identified in PR1 cells. Upregulation of wild-type EGFR signaling identified in PR2 cells.

2017-04-21 | GSE98030 | GEO

ena-DATASET-RTL-03-05-2017-12:40:06:735-476 - samples

Project description:RNAseq of LC2AD with AD80 or DMSO Plenker et al., Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

| EGAD00001003316 | EGA

RNA-seq of RET-aberrant cancer cell lines treated with RET-TKI selpercatinib

Project description:RET-aberrant cancer discovered as a relevant targetable oncogene in several types of tumors, whose inhibitors have marked efficacy. However, some of patients with RET-aberrant cancer are insensitive to RET- tyrosine kinase inhibitors (TKIs) and are clinically non-responders. Recently, drug-tolerant mechanisms have been gaining attention as targets for initial therapies aimed at overcoming drug resistance. However, the underlying mechanisms of drug-tolerant cells emergence treated with RET-TKIs derived from RET-aberrant cancer cells remains unknown. In this study, HER3 signal activity through YAP1 was led to maintaining cell survival and inducing the emergence of cells tolerant to RET-TKIs selpercatinib and pralsetinib in high YAP1 expressed RET- rearranged cancer cells. These results suggested that YAP1-HER3 axis plays pivotal roles for cell survival under an exposure with RET-TKIs in the intrinsic resistance to RET-TKIs and the emergence of tolerant cells by RET-TKIs in YAP1 expressed RET-aberrant cancer, suggesting that YAP1/HER3 inhibition and RET-TKIs is a highly potent combination for initial treatment.

2024-09-30 | GSE261830 | GEO

Enhancer-activated RET confers protection against oxidative stress to the MLL-rearranged acute myeloid leukemia cells

Project description:RET expression is upregulated in AML subtypes harboring genetic fusions of MLL-1 genes compared to age-matched healthy donors and other AML subtypes. In addition, we identify a novel epigenetic mechanism of RET overexpression in MLL-rearranged AML.

2024-03-04 | GSE241738 | GEO

Genes expression alterations associated with resistance to combined CDK4/6 inhibitor and endocrine therapy in ER+ breast cancer

Project description:Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and resultant disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored. To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed global gene expression analysis and RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy.

2024-11-19 | GSE268699 | GEO

Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

Project description:Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

| EGAS00001002335 | EGA

Homo sapiens

Project description:Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

| PRJNA284924 | ENA

IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets Ras-MAP Kinase Driven Tumors

Project description:MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer. Gene expression profiling: Fragmented cRNA was hybridized to the Mouse Gene 1.0 ST Array (Affymetrix). Iqgap1 wild-type and Iqgap1 knockout mouse treated with topical 4OHT for 0 days and 6 days days are compared.

2013-04-01 | E-GEOD-44967 | biostudies-arrayexpress

Transcriptomes analysis of mammary tumors induced by overexpression of the Ret receptor tyrosine kinase from a new transgenic mouse model

Project description:Model: The activation of Ret receptor tyrosine kinase regulates mammary tumor growth, tumor-associated inflammation and metastasis. To uncover Ret’s function, we have generated a new transgenic mouse mammary tumor model, in which the human wild type Ret is expressed in the mammary epithelium of mice in a doxycycline (Dox)-inducible manner (system developed by Dr. Chosdosh). Induction of constitutive Ret expression leads to the development of mammary tumors in 60% of the mice. We have found that the Ret-induced tumors have histologic characteristics of the human DCIS. Purpose: The goals of this study are to compare Next-generation sequencing (NGS)-derived transcriptome profiling (RNA-seq) of Ret-induced tumors to human breast cancer databases in order to determined which cancer subtype is represented by this new tumor model. Additionally, to further analyze the mechanisms underlying Ret-induced tumorigenesis, we will also examine the transcriptome by NGS: in this case, this analysis will be performed on tumors that regress upon dox-food withdrawal, in comparison to the growing tumors. We will also perform similar analysis with the hyperplastic glands, a step before of tumor development. Later, the RNA-seq differential expression data will be analyzed using pathway analysis software as Ingenuity and public available datasets as the Gene Set Enrichment Analysis (GSEA) or the Integrating Motif Response Activity Analysis (ISMARA).

2019-06-30 | GSE83897 | GEO

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