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1.
Clin Cancer Res ; 24(15): 3550-3559, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29588308

ABSTRACT

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice.Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550-9. ©2018 AACR.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Colorectal Neoplasms/genetics , Neovascularization, Pathologic/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Anaplastic Lymphoma Kinase/genetics , Angiogenesis Inhibitors/adverse effects , Animals , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/genetics , Exome/genetics , Female , Heterografts , Humans , Mice , Mutation , Neovascularization, Pathologic/blood , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Protein Conformation/drug effects , Proto-Oncogene Proteins c-abl/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/blood , Vascular Endothelial Growth Factor Receptor-2/chemistry , Exome Sequencing
2.
Cell Cycle ; 5(16): 1880-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16929179

ABSTRACT

The p53 protein is a sequence-specific transcription factor that plays a crucial role in tumor suppression by inducing apoptosis or cell cycle arrest in response to cellular damage. To identify novel proteins involved in the regulation of p53 transcriptional activity we have performed a large scale RNA interference-based screen. We have identified four genes previously unknown to be involved in modulating p53 activity (GAS41, RPS6K4, RUNDC1 and CRMP-2). The interference of each of these four genes resulted in the upregulation of p53 transcriptional activity and, conversely, their overexpression resulted in the inhibition of p53 target promoters and p53-mediated apoptosis. These observations suggest a role for these genes as p53 inhibitors and imply that they may have oncogenic activity.


Subject(s)
RNA Interference , Transcription, Genetic , Tumor Suppressor Protein p53/metabolism , Apoptosis/genetics , Cell Line, Tumor , Genes, Reporter , Humans , Intercellular Signaling Peptides and Proteins , Intracellular Signaling Peptides and Proteins , Luciferases , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins/genetics , RNA, Small Interfering , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection , Tumor Suppressor Protein p53/genetics
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