2. Academic Validation
  3. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis

Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis

  • EBioMedicine. 2018 Mar;29:112-127. doi: 10.1016/j.ebiom.2018.02.001.
Niki Karachaliou 1,  Imane Chaib 2,  Andres Felipe Cardona 3,  Jordi Berenguer 4,  Jillian Wilhelmina Paulina Bracht 4,  Jie Yang 5,  Xueting Cai 5,  Zhigang Wang 5,  Chunping Hu 5,  Ana Drozdowskyj 6,  Carles Codony Servat 4,  Jordi Codony Servat 4,  Masaoki Ito 7,  Ilaria Attili 8,  Erika Aldeguer 4,  Ana Gimenez Capitan 4,  July Rodriguez 9,  Leonardo Rojas 9,  Santiago Viteri 10,  Miguel Angel Molina-Vila 4,  Sai-Hong Ignatius Ou 11,  Morihito Okada 12,  Tony S Mok 13,  Trever G Bivona 14,  Mayumi Ono 15,  Jean Cui 16,  Santiago Ramón Y Cajal 17,  Alex Frias 18,  Peng Cao 19,  Rafael Rosell 20
Affiliations

Affiliations

  • 1 Instituto 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, Spain.
  • 2 Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain.
  • 3 Clinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, Colombia; Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia.
  • 4 Pangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, Spain.
  • 5 Affiliated 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.
  • 6 Pivotal, Madrid, Spain.
  • 7 Pangaea 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, Japan.
  • 8 Pangaea 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, Italy.
  • 9 Clinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, Colombia.
  • 10 Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain.
  • 11 Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, United States.
  • 12 Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
  • 13 The 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 Kong.
  • 14 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States.
  • 15 Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • 16 TP Therapeutics, Inc., San Diego, CA, United States.
  • 17 Pathology Department, Vall d'Hebrón University Hospital, Spain.
  • 18 Brain Tumor Biology, Danish Cancer Society Research Center, Denmark.
  • 19 Affiliated 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. Electronic address: pcao79@yahoo.com.
  • 20 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. Electronic address: rrosell@iconcologia.net.
PMID: 29433983 DOI: 10.1016/j.ebiom.2018.02.001
Abstract

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

AXL; CDCP1; Combination therapies; EGFR; Lung cancer; Resistance.

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