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

Authors :
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
Source :
EBioMedicine, Vol 29, Iss , Pp 112-127 (2018)
Publication Year :
2018
Publisher :
Elsevier, 2018.

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: Lung cancer, EGFR, Resistance, AXL, CDCP1, Combination therapies

Subjects

Subjects :
Medicine
Medicine (General)
R5-920

Details

Language :
English
ISSN :
23523964
Volume :
29
Issue :
112-127
Database :
Directory of Open Access Journals
Journal :
EBioMedicine
Publication Type :
Academic Journal
Accession number :
edsdoj.4a85629cde14b10a642cf79a55d7f2c
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ebiom.2018.02.001