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Updated: May 20, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

CAMK2D isoform 15 facilitates gefitinib resistance via AKT phosphorylation in lung adenocarcinoma

Lingmei Li1, Danyang Ren2, Yutian Wang1

  • 1Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, China.

Cancer Biology & Medicine
|May 19, 2026
PubMed
Abstract

Insights

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma is linked to CAMK2D isoform 15. This isoform activates AKT signaling, promoting resistance, and is regulated by SNRPA1, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) poses a significant challenge in treating lung adenocarcinoma (LUAD).
  • Epidermal growth factor receptor (EGFR) signaling activates calcium/calmodulin-dependent protein kinase 2 (CAMK2), but its role in TKI resistance remains unclear.

Purpose of the Study:

  • Investigate the role of calcium/calmodulin-dependent protein kinase II delta (CAMK2D) splice variants in gefitinib resistance in LUAD.
  • Identify upstream regulators of CAMK2D splicing and elucidate the underlying mechanism of TKI resistance.

Main Methods:

  • Analysis of clinical LUAD specimens and TKI-exposed cell lines.
  • Evaluation of CAMK2D isoform 15 effects using in vitro and in vivo xenograft models.
  • Integrative multi-omics analysis to identify splicing regulators.

Main Results:

  • CAMK2D overexpression, specifically isoform 15 (containing exon 7), strongly correlated with EGFR-TKI resistance.
  • CAMK2D isoform 15 enhanced gefitinib resistance and tumor growth, while its knockdown restored sensitivity.
  • CAMK2D isoform 15 activated AKT signaling by promoting AKT phosphorylation at Thr308, enhancing anti-apoptotic pathways.
  • Small nuclear ribonucleoprotein polypeptide A1 (SNRPA1) was identified as a key upstream regulator, with its downregulation promoting CAMK2D isoform 15 expression and resistance.

Conclusions:

  • SNRPA1-controlled alternative splicing of CAMK2D drives EGFR-TKI resistance in LUAD by promoting CAMK2D isoform 15 expression.
  • CAMK2D isoform 15 activates AKT signaling, leading to gefitinib resistance.
  • CAMK2D isoform 15 is a potential prognostic biomarker and therapeutic target for overcoming TKI resistance in LUAD, suggesting splicing-directed strategies.
Keywords:
Lung adenocarcinomaalternative splicingcalcium/calmodulin-dependent protein kinase 2D isoform 15epidermal growth factor receptor

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