Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA120533 | ENA |
REPOSITORIES: ENA
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Project description:Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. Yet, there are cases in which cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependency results in tumor regression upon oncogene inactivation (‘oncogene addiction’). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this drastic response to oncogene neutralization is crucial to identify the vulnerabilities of cancer. We combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in a variety of cancer cells addicted to tyrosine kinase receptor oncogenes, using the Met receptor as the major model system. Unexpectedly, we found that Met blockade impacts on a limited subset of Met downstream signals: little or no effect was observed for many relevant pathways controlling Met-driven neoplastic growth – such as STATs, NF-kB, JNK, and p38 MAPK – and only a restricted and pathway-specific signature of Ras/PI3K transducers and transcriptional effectors was fully neutralized. An analogous signature was also generated by EGF receptor inhibition in a different cellular context, suggesting a stereotyped response that likely does not depend on receptor type or tissue origin. Biologically, cell-cycle arrest induced by Met de-activation was recapitulated by extinction of Ras/PI3K-dependent signals and was rescued by active forms of the same signals. These findings uncover ‘dominant’ and ‘recessive’ nodes among the numerous oncogenic networks regulated by tyrosine kinase receptors and active in cancer, with the Ras/PI3K pathways being the necessary and sufficient determinants of therapeutic response.
2010-03-01 | GSE19043 | GEO
Project description:Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction remain largely unexplored. We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models and ex vivo non-small cell lung cancer patient organotypic cultures. We identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.
2023-03-11 | PXD037406 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE27389: Substitutions in the KRas oncogene determine protein behavior: Implications for signaling and clinical outcome. GSE31428: Final efficacy and biomarker analysis of the sorafenib arm of the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial GSE31852: An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET. GSE33072: An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to erlotinib and PI3K pathway inhibitors and identifies Axl as a novel EMT marker in non-small cell lung cancer. Refer to individual Series
2012-01-01 | E-GEOD-31437 | biostudies-arrayexpress
Project description:This experiment investigates In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. The goal of this study was to examine the effects of AMG337 on proliferation in cancer cell lines with varying MET copy number, the hypothesis being that high-level focal MET amplification is required to confer MET oncogene addiction and AMG337 sensitivity.
2016-05-04 | GSE77414 | GEO
Project description:The Ras/ERK and PI3K/AKT pathways differentially regulate the oncogene ERG in prostate cancer resulting in differential transcriptional profile
2021-05-27 | GSE164859 | GEO
Project description:Here, using a quantitative autochthonous mouse model system and performing iterative in vivo functional screens (mainly with programmable multiplexed CRISPR/Cas9-induced genotypes via ultra-deep sequencing of DNA barcoded tumors: Tuba-seq), we uncover genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Through the generation of hundreds of diverse combinatorial tumor suppressor alterations, we demonstrate that inactivation of suppressors of the RAS/MAPK and PI3K pathways allows for stepwise and efficient acquisition of growth advantage that can drive the development of oncogene-negative lung adenocarcinoma. Furthermore, we demonstrate that oncogene-negative tumors with activated RAS/MAPK and PI3K pathways are vulnerable to pharmacological inhibition of these signaling axes.
2022-03-08 | GSE174393 | GEO
Project description:MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT (survival/migration), STAT3 (differentiation), and MAPK (proliferation). When mutated or amplified, MET becomes a "driver" for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to its "skipping" from mRNA and consequent deletion of the receptor's juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared to WT MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response, ultimately leading to a robust phosphorylation of AKT, without affecting MAPK or STAT3. This altered kinase response leads to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.
2022-05-27 | GSE194382 | GEO
Project description:Mechanism of Oncogene Addiction
| PRJNA302297 | ENA
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies. Affymetrix SNP array analysis was performed with Mouse Diversity Genotyping Arrays (Affymetrix) on genomic DNA extracted from frozen biopsies of 6 recurrent mouse mammary tumor samples. Copy number analysis was performed for the mouse mammary tumors using genomic DNA from normal mammary tissue as the reference for copy number inference.
2011-08-01 | E-GEOD-27691 | biostudies-arrayexpress
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies.
2011-08-02 | GSE27691 | GEO