CD44 facilitates epithelial-to-mesenchymal transition phenotypic change at acquisition of resistance to EGFR kinase inhibitors in lung cancer

Kenichi Suda, Isao Murakami, Hui Yu, Jihye Kim, Aik-Choon Tan, Hiroshi Mizuuchi, Leslie Rozeboom, Kim Ellison, Christopher J. Rivard, Tetsuya Mitsudomi, Fred R. Hirsch

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Epithelial-to-mesenchymal transition (EMT) is one of the acquired resistance mechanisms to EGFR tyrosine kinase inhibitors (TKI) in lung cancers. Because EMT is related to tumor invasion, metastases, and resistance to various treatments, it is important to prevent the emergence of EMT. However, molecular mechanism(s) underlying EMT phenotypic changes, as well as biomarker(s) that predict the emergence of EMT in EGFR-mutated lung cancers, are unclear to date. Through the comparison of expression data between isogenic lung cancer cell lines that acquired resistance to EGFR-TKI(s), we identified that high CD44 expression is related to a mesenchymal phenotype and that shRNA-mediated knockdown of CD44 reversed the EMT change. High membranous CD44 expression was identified in lesions with mesenchymal phenotype that were obtained from lung cancer patients who developed acquired resistance to gefitinib or afatinib, whereas isogenic lesions without EMT change showed negative/weak staining for CD44. Immunohistochemistry for treatment-na€ve lung cancer cell lines with EGFR mutations found those that acquire resistance to EGFR-TKIs via EMT (HCC4006 and H1975 cells) had strong membranous CD44 expression compared with non-EMT-transforming lines which demonstrated negative or weak staining (Fisher exact test P value ¼ 0.036). shRNA-mediated CD44 knockdown in HCC4006 cells prevented the emergence of EMT after chronic exposure to osimertinib. These results suggest that upregulation of CD44 facilitates EMT-phenotypic change in lung cancers with EGFR mutations when treated with EGFR-TKIs. In addition, our results suggest that CD44 can be a useful biomarker to predict the emergence of EMT upon EGFR-TKI monotherapy.

Original languageEnglish
Pages (from-to)2257-2265
Number of pages9
JournalMolecular Cancer Therapeutics
Volume17
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1
Externally publishedYes

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Epithelial-Mesenchymal Transition
Lung Neoplasms
Phosphotransferases
Protein-Tyrosine Kinases
Small Interfering RNA
Biomarkers
Phenotype
Cell Line
Negative Staining
Mutation
Up-Regulation
Immunohistochemistry
Staining and Labeling
Neoplasm Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

CD44 facilitates epithelial-to-mesenchymal transition phenotypic change at acquisition of resistance to EGFR kinase inhibitors in lung cancer. / Suda, Kenichi; Murakami, Isao; Yu, Hui; Kim, Jihye; Tan, Aik-Choon; Mizuuchi, Hiroshi; Rozeboom, Leslie; Ellison, Kim; Rivard, Christopher J.; Mitsudomi, Tetsuya; Hirsch, Fred R.

In: Molecular Cancer Therapeutics, Vol. 17, No. 10, 01.10.2018, p. 2257-2265.

Research output: Contribution to journalArticle

Suda, K, Murakami, I, Yu, H, Kim, J, Tan, A-C, Mizuuchi, H, Rozeboom, L, Ellison, K, Rivard, CJ, Mitsudomi, T & Hirsch, FR 2018, 'CD44 facilitates epithelial-to-mesenchymal transition phenotypic change at acquisition of resistance to EGFR kinase inhibitors in lung cancer', Molecular Cancer Therapeutics, vol. 17, no. 10, pp. 2257-2265. https://doi.org/10.1158/1535-7163.MCT-17-1279
Suda, Kenichi ; Murakami, Isao ; Yu, Hui ; Kim, Jihye ; Tan, Aik-Choon ; Mizuuchi, Hiroshi ; Rozeboom, Leslie ; Ellison, Kim ; Rivard, Christopher J. ; Mitsudomi, Tetsuya ; Hirsch, Fred R. / CD44 facilitates epithelial-to-mesenchymal transition phenotypic change at acquisition of resistance to EGFR kinase inhibitors in lung cancer. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 10. pp. 2257-2265.
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