Inhibition of DCLK1 sensitizes resistant lung adenocarcinomas to EGFR-TKI through suppression of Wnt/β-Catenin activity and cancer stemness.

Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE

Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.

Adenocarcinoma of Lung*/drug therapy ; Adenocarcinoma of Lung*/genetics ; Carcinoma, Non-Small-Cell Lung*/drug therapy ; Carcinoma, Non-Small-Cell Lung*/genetics ; Carcinoma, Non-Small-Cell Lung*/metabolism ; Lung Neoplasms*/drug therapy ; Lung Neoplasms*/genetics ; Lung Neoplasms*/metabolism; Cell Line, Tumor ; Doublecortin-Like Kinases ; Drug Resistance, Neoplasm ; ErbB Receptors/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/pharmacology ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/genetics ; Receptors, Growth Factor/genetics ; beta Catenin/genetics

Lung adenocarcinoma is the most common form of lung cancer, accounting for 60% of non-small cell lung cancer (NSCLC) cases in Asian patients. Importantly, nearly half of these patients have epithelial growth factor receptor (EGFR) mutations. Though EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line therapy for NSCLC patients, the development of resistance reduces their efficiency and limits their application. As the complicated and heterogeneous mechanism of acquired resistance among individuals, the efficiency of anti-angiogenesis therapy, immune checkpoint inhibitors, or chemo-radiotherapies is rather less promising. In this research, we investigated the role of the tumor stem cell marker DCLK1 in EGFR-TKI resistance of lung adenocarcinoma. We discovered that DCLK1 was critical in maintaining the stemness of tumor cells through the Wnt/β-Catenin pathway, which was conducive to the development of EGFR-TKI resistance. Inhibiting DCLK1 activity restored the sensitivity of TKI-resistant tumor cells and organoids. Moreover, our study showed that DCLK1 inhibitor had a synergistic effect in controlling tumor growth when combined with EGFR-TKIs. Overall, our study provides new insights into EGFR-TKI resistant lung adenocarcinoma through inhibition of DCLK1 expression.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Keywords: DCLK1; EGFR; Lung adenocarcinoma; TKI-Resistance

0 (Intracellular Signaling Peptides and Proteins)
0 (Protein Kinase Inhibitors)
0 (Receptors, Growth Factor)
0 (beta Catenin)
EC 2.7.1.11 (DCLK1 protein, human)
EC 2.7.1.11 (Doublecortin-Like Kinases)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)

Date Created: 20220214 Date Completed: 20220422 Latest Revision: 20220422

20221213

10.1016/j.canlet.2022.01.030

35157971