دورية أكاديمية
Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras -Mutant Lung Cancers.
| العنوان: | Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras -Mutant Lung Cancers. |
|---|---|
| المؤلفون: | Talwelkar SS; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Nagaraj AS; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Devlin JR; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Hemmes A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Potdar S; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Kiss EA; University of Helsinki and Wihuri Research Institute, Helsinki, Finland., Saharinen P; University of Helsinki and Wihuri Research Institute, Helsinki, Finland., Salmenkivi K; HUSLAB, Division of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Mäyränpää MI; HUSLAB, Division of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.; Department of Pathology, University of Helsinki, Helsinki, Finland., Wennerberg K; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Verschuren EW; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. emmy.verschuren@helsinki.fi. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2019 Oct; Vol. 18 (10), pp. 1863-1874. Date of Electronic Publication: 2019 Jul 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Signal Transduction*, ErbB Receptors/*antagonists & inhibitors , Lung Neoplasms/*genetics , Mutation/*genetics , Proto-Oncogene Proteins p21(ras)/*genetics , Receptor Protein-Tyrosine Kinases/*metabolism, Animals ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Line, Tumor ; Cell Proliferation ; Enzyme Activation ; ErbB Receptors/metabolism ; Genotype ; Humans ; Lung Neoplasms/drug therapy ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism |
| مستخلص: | Most non-small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53 , or STK11/LKB1 alterations. By coupling ex vivo drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from Kras G12D/+ ;Lkb1 fl/fl (KL) tumors or AC cultures from Kras G12D/+ ;p53 fl/fl (KP) tumors. Although p53 -null cells readily propagated as conventional cultures, Lkb1 -null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition. (©2019 American Association for Cancer Research.) |
| المشرفين على المادة: | 0 (KRAS protein, human) EC 2.7.10.1 (ErbB Receptors) EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) |
| تواريخ الأحداث: | Date Created: 20190720 Date Completed: 20200609 Latest Revision: 20200930 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1158/1535-7163.MCT-18-0573 |
| PMID: | 31320402 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
|---|---|
| DOI: | 10.1158/1535-7163.MCT-18-0573 |