Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell 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 modifier...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418300501 |
| _version_ | 1819037786129301504 |
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| author | Niki Karachaliou Imane Chaib Andres Felipe Cardona Jordi Berenguer Jillian Wilhelmina Paulina Bracht Jie Yang Xueting Cai Zhigang Wang Chunping Hu Ana Drozdowskyj Carles Codony Servat Jordi Codony Servat Masaoki Ito Ilaria Attili Erika Aldeguer Ana Gimenez Capitan July Rodriguez Leonardo Rojas Santiago Viteri Miguel Angel Molina-Vila Sai-Hong Ignatius Ou Morihito Okada Tony S. Mok Trever G. Bivona Mayumi Ono Jean Cui Santiago Ramón y Cajal Peng Cao Rafael Rosell |
| author_facet | Niki Karachaliou Imane Chaib Andres Felipe Cardona Jordi Berenguer Jillian Wilhelmina Paulina Bracht Jie Yang Xueting Cai Zhigang Wang Chunping Hu Ana Drozdowskyj Carles Codony Servat Jordi Codony Servat Masaoki Ito Ilaria Attili Erika Aldeguer Ana Gimenez Capitan July Rodriguez Leonardo Rojas Santiago Viteri Miguel Angel Molina-Vila Sai-Hong Ignatius Ou Morihito Okada Tony S. Mok Trever G. Bivona Mayumi Ono Jean Cui Santiago Ramón y Cajal Peng Cao Rafael Rosell |
| author_sort | Niki Karachaliou |
| collection | DOAJ |
| description | Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell 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. Keywords: Lung cancer, EGFR, Resistance, AXL, CDCP1, Combination therapies |
| first_indexed | 2024-12-21T08:26:57Z |
| format | Article |
| id | doaj.art-d4a85629cde14b10a642cf79a55d7f2c |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T08:26:57Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-d4a85629cde14b10a642cf79a55d7f2c2022-12-21T19:10:18ZengElsevierEBioMedicine2352-39642018-03-0129112127Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor PrognosisNiki Karachaliou0Imane Chaib1Andres Felipe Cardona2Jordi Berenguer3Jillian Wilhelmina Paulina Bracht4Jie Yang5Xueting Cai6Zhigang Wang7Chunping Hu8Ana Drozdowskyj9Carles Codony Servat10Jordi Codony Servat11Masaoki Ito12Ilaria Attili13Erika Aldeguer14Ana Gimenez Capitan15July Rodriguez16Leonardo Rojas17Santiago Viteri18Miguel Angel Molina-Vila19Sai-Hong Ignatius Ou20Morihito Okada21Tony S. Mok22Trever G. Bivona23Mayumi Ono24Jean Cui25Santiago Ramón y Cajal26Peng Cao27Rafael Rosell28Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, QuironSalud Group, Barcelona, Spain; Pangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainInstitut d'Investigació en Ciències Germans Trias i Pujol, Badalona, SpainClinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, Colombia; Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, ColombiaPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, ChinaAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, ChinaAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, ChinaAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, ChinaPivotal, Madrid, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, Spain; Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, Spain; Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, ItalyPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainClinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, ColombiaClinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, ColombiaInstituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, SpainDepartment of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, United StatesDepartment of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanThe State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong KongUCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United StatesDepartment of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, JapanTP Therapeutics, Inc., San Diego, CA, United StatesPathology Department, Vall d'Hebrón University Hospital, SpainAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, China; Correspondence to: P. Cao, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, China.Pangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, Spain; Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain; Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain; Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Correspondence to: R. Rosell, Institut Catalá d´Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain.Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell 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. Keywords: Lung cancer, EGFR, Resistance, AXL, CDCP1, Combination therapieshttp://www.sciencedirect.com/science/article/pii/S2352396418300501 |
| spellingShingle | Niki Karachaliou Imane Chaib Andres Felipe Cardona Jordi Berenguer Jillian Wilhelmina Paulina Bracht Jie Yang Xueting Cai Zhigang Wang Chunping Hu Ana Drozdowskyj Carles Codony Servat Jordi Codony Servat Masaoki Ito Ilaria Attili Erika Aldeguer Ana Gimenez Capitan July Rodriguez Leonardo Rojas Santiago Viteri Miguel Angel Molina-Vila Sai-Hong Ignatius Ou Morihito Okada Tony S. Mok Trever G. Bivona Mayumi Ono Jean Cui Santiago Ramón y Cajal Peng Cao Rafael Rosell Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis EBioMedicine |
| title | Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis |
| title_full | Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis |
| title_fullStr | Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis |
| title_full_unstemmed | Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis |
| title_short | Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis |
| title_sort | common co activation of axl and cdcp1 in egfr mutation positive non smallcell lung cancer associated with poor prognosis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418300501 |
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