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Updated: Aug 13, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeted nanoparticle-mediated Co-delivery of IFITM3 KO and ponatinib reverses TKI resistance in chronic myeloid
Zhenyang Feng1, Yaofang Ma1, Jiahui Hu1
1School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Abstract:
Resistance to tyrosine kinase inhibitors (TKIs) is a core limitation in the clinical treatment of chronic myeloid leukemia (CML). Although ponatinib can cover the T315I mutation, its clinical application is limited by severe adverse reactions at high doses. On the basis of the USP28-BCR-ABL-IFITM3 resistance signaling axis first identified in our previous study, a ginger-derived lipid carrier-mediated targeted nanodelivery system (IP@GLPs@εF) was constructed, which codelivers CRISPR/Cas9-mediated IFITM3 knockout (IFITM3 KO) plasmid and ponatinib, establishing a new synergistic intervention mode of gene editing and targeted chemotherapy. When modified with ε-polylysine and fucoidan via layer-by-layer self-assembly technology, the carrier has an average particle size of 226.1 nm, a drug encapsulation efficiency of 84.2%, and excellent biocompatibility. In vitro experiments confirmed that the optimal ratio (2.5 μg IFITM3-sg3 + 5 μM ponatinib) significantly reversed the drug resistance of K562R cells, promoted apoptosis and inhibited proliferation. In vivo experiments using ectopic and orthotopic xenograft models verified that this system can efficiently target tumor tissues and significantly suppress the progression and metastasis of drug-resistant tumors, with no obvious toxic side effects on major organs. Mechanistically, this study revealed that IFITM3 mediates CML resistance by interacting with HSPA9 to activate the MET/AKT/BCL2 pathway and that IFITM3 KO can block this pathway and exert a synergistic antiresistance effect with ponatinib. This research provides a novel IFITM3-targeted synergistic therapeutic strategy and technical support for the clinical treatment of CML resistance.
Insights
A novel nanodelivery system combines gene editing and chemotherapy to overcome tyrosine kinase inhibitor resistance in chronic myeloid leukemia (CML). This approach targets the IFITM3 protein, offering a promising strategy for treating resistant CML.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Tyrosine kinase inhibitor (TKI) resistance is a major challenge in chronic myeloid leukemia (CML) treatment.
- Ponatinib is effective against the T315I mutation but has dose-limiting toxicities.
- A previously identified USP28-BCR-ABL-IFITM3 signaling axis contributes to TKI resistance.
Purpose of the Study:
- To develop a targeted nanodelivery system for synergistic gene editing and chemotherapy in TKI-resistant CML.
- To investigate the efficacy of codelivering IFITM3 knockout plasmid and ponatinib using a ginger-derived lipid carrier.
- To elucidate the mechanism of IFITM3-mediated resistance and the synergistic effect of IFITM3 knockout and ponatinib.
Main Methods:
- Construction of a ginger-derived lipid carrier (IP@GLPs@εF) for codelivering IFITM3 knockout plasmid and ponatinib.
- Layer-by-layer self-assembly modification with ε-polylysine and fucoidan.
- In vitro evaluation of drug resistance reversal, apoptosis promotion, and proliferation inhibition in K562R cells.
- In vivo assessment of tumor targeting, suppression of progression and metastasis in xenograft models.
- Mechanistic studies on the role of IFITM3, HSPA9, and the MET/AKT/BCL2 pathway.
Main Results:
- The developed nanocarrier exhibited optimal particle size, high drug encapsulation efficiency, and excellent biocompatibility.
- In vitro studies demonstrated significant reversal of drug resistance, enhanced apoptosis, and inhibited proliferation in resistant CML cells.
- In vivo experiments showed efficient tumor targeting, suppressed tumor progression and metastasis, and minimal toxicity to major organs.
- IFITM3 was found to mediate CML resistance by interacting with HSPA9 and activating the MET/AKT/BCL2 pathway.
Conclusions:
- The novel IFITM3-targeted nanodelivery system effectively overcomes TKI resistance in CML through synergistic gene editing and chemotherapy.
- IFITM3 knockout blocks the MET/AKT/BCL2 pathway, enhancing the antiresistance effect of ponatinib.
- This strategy provides a new therapeutic approach and technical support for managing CML resistance.
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