Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis
| Autor: | Jean Cui, Miguel Angel Molina-Vila, Jordi Codony Servat, Ana Gimenez Capitan, Ilaria Attili, Rafael Rosell, Masaoki Ito, Zhigang Wang, Niki Karachaliou, Sai-Hong Ignatius Ou, Santiago Ramón y Cajal, Jillian Wilhelmina Paulina Bracht, Jordi Berenguer, Jie Yang, Santiago Viteri, Trever G. Bivona, Imane Chaib, Peng Cao, Andrés F. Cardona, Ana Drozdowskyj, Carles Codony Servat, Chunping Hu, Erika Aldeguer, Morihito Okada, Mayumi Ono, Xueting Cai, July Rodriguez, Alex Frias, Tony Mok, Leonardo Rojas |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Proteomics Lung Neoplasms CDCP1 Resistance Drug Resistance lcsh:Medicine Receptor tyrosine kinase Mice 0302 clinical medicine Models Carcinoma Non-Small-Cell Lung 80 and over Medicine Osimertinib Epidermal growth factor receptor RNA Small Interfering Non-Small-Cell Lung Lung Cancer Aged 80 and over lcsh:R5-920 Janus kinase 2 biology Kinase General Medicine Middle Aged 3. Good health CD Neoplasm Proteins ErbB Receptors Gene Expression Regulation Neoplastic 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Public Health and Health Services Female Development of treatments and therapeutic interventions Lung cancer lcsh:Medicine (General) medicine.drug Proto-oncogene tyrosine-protein kinase Src Research Paper Adult Cell Survival EGFR Clinical Sciences and over Small Interfering Models Biological General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Gefitinib Antigens CD Antigens Neoplasm Proto-Oncogene Proteins Animals Humans Antigens Aged Neoplastic business.industry Animal Gene Expression Profiling lcsh:R Carcinoma Receptor Protein-Tyrosine Kinases AXL medicine.disease Biological Survival Analysis Xenograft Model Antitumor Assays Axl Receptor Tyrosine Kinase respiratory tract diseases Enzyme Activation Disease Models Animal 030104 developmental biology Gene Expression Regulation Drug Resistance Neoplasm Disease Models Mutation Cancer research biology.protein RNA Neoplasm Combination therapies business Cell Adhesion Molecules |
| Zdroj: | EBioMedicine EBioMedicine, Vol 29, Iss, Pp 112-127 (2018) |
| ISSN: | 2352-3964 |
| Popis: | Epidermal growth factor receptor (EGFR)-mutation-positive non-small cell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p = 0.0407) and overall survival (hazard ratio of 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing. Graphical Abstract Unlabelled Image Highlights • AXL and CDCP1 are co-expressed in treatment-naïve EGFR-mutation-positive NSCLC patients. • AXL and CDCP1 are related to shorter progression-free survival with EGFR inhibitors and shorter overall survival. • Src family kinases and YAP1 are regulatory nodes for AXL and CDCP1 expression. • The combination of EGFR TKI with TPX-0005 is synergistic in EGFR-mutation-positive lung tumors in culture and in vivo. We explore the molecular changes that occur after the application of an EGFR inhibitor in EGFR-mutation positive tumors. The tumors do not acquire secondary drivers to overcome a primary driver but, counter-regulatory nodes observable before treatment, are immediately made apparent by pathway-specific intervention. The expression of the receptor tyrosine kinase AXL and the transmembrane protein CDCP1 in baseline samples of EGFR-mutation positive NSCLC patients can provide us with information on the treatment outcome. The upfront combination of an EGFR inhibitor with a multikinase inhibitor, that controls the regulatory nodes for RTKs activation, is a therapeutic approach that deserves to be further explored. |
| Databáze: | OpenAIRE |
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