CD44s and CD44v8-10 isoforms confer acquired resistance to osimertinib by activating the ErbB3/STAT3 signaling pathway

Yi-Nan Liu; Meng-Feng Tsai; Shang-Gin Wu; Tzu-Hua Chang; Jin-Yuan Shih

doi:10.1016/j.lfs.2023.122345

CD44s and CD44v8-10 isoforms confer acquired resistance to osimertinib by activating the ErbB3/STAT3 signaling pathway

Life Sci. 2024 Jan 1:336:122345. doi: 10.1016/j.lfs.2023.122345. Epub 2023 Dec 11.

Authors

Yi-Nan Liu¹, Meng-Feng Tsai², Shang-Gin Wu³, Tzu-Hua Chang¹, Jin-Yuan Shih⁴

Affiliations

¹ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan.
³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Cancer Center, Taipei, Taiwan.
⁴ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: jyshih@ntu.edu.tw.

PMID: 38092140
DOI: 10.1016/j.lfs.2023.122345

Abstract

Aims: Although epidermal growth factor receptor (EGFR)-mutant lung cancers respond well to osimertinib, acquired resistance to osimertinib eventually develops through EGFR-dependent and EGFR-independent resistance mechanisms. CD44 splicing variants are widely expressed in lung cancer tissues. However, it remains unclear whether specific splicing variants are involved in acquired resistance to osimertinib.

Main methods: The real-time PCR was performed to measure the expression levels of total CD44 and specific CD44 splicing variants (CD44s or CD44v). Gene knockdown and restoration were performed to investigate the effects of CD44 splicing variants on osimertinib sensitivity. Activation of the signaling pathway was evaluated using receptor-tyrosine-kinase phosphorylation membrane arrays, co-immunoprecipitation, and western blotting.

Key findings: Clinical analysis demonstrated that the expression level of total CD44 increased in primary cancer cells from lung adenocarcinomas patients after the development of acquired resistance to osimertinib. Furthermore, osimertinib-resistant cells showed elevated levels of either the CD44s variant or CD44v variants. Manipulations of CD44s or CD44v8-10 were performed to investigate their effects on treatment sensitivity to osimertinib. Knockdown of CD44 increased osimertinib-induced cell death in osimertinib-resistant cells. However, restoration of CD44s or CD44v8-10 in CD44-knockdown H1975/AZD-sgCD44 cells induced osimertinib resistance. Mechanically, we showed that ErbB3 interacted with CD44 and was transactivated by CD44, that consequently triggered activation of the ErbB3/STAT3 signaling pathway and led to CD44s- or CD44v8-10-mediated osimertinib resistance.

Significance: CD44 is a co-receptor for ErbB3 and triggers activation of the ErbB3 signaling axis, leading to acquired resistance to osimertinib. CD44/ErbB3 signaling may represent a therapeutic target for overcoming osimertinib resistance.

Keywords: Acquired resistance; CD44 isoform; Lung cancer; Osimertinib.

MeSH terms

Aniline Compounds / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
ErbB Receptors / genetics
ErbB Receptors / metabolism
Humans
Hyaluronan Receptors / genetics
Hyaluronan Receptors / metabolism
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Protein Isoforms / genetics
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction

Substances

osimertinib
Protein Isoforms
Aniline Compounds
ErbB Receptors
Hyaluronan Receptors
CD44 protein, human
STAT3 protein, human
STAT3 Transcription Factor