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ORIGINAL RESEARCH

Overcoming gefitinib resistance and metastasis in adenocarcinoma through synergistic PI3K–AKT–ERK blockade: Integrated rational co-delivery nanoplatform and multimodel validation

Jialong Deng1,2# ,  Bin Xu3# ,  Huili Wang4# ,  Weihuan Lin5 ,  Hengliang Hou2,3 ,  Shengbo Liu1,2 ,  Yucheng Huang2,3 ,  Zenan Lin2 ,  Qiaxuan Li2 ,  Hongrui Qiu2,4 ,  Chaodong Wu6 ,  Yubo Zhou7 ,  Fanjun Zeng5* ,  Lintong Yao2* ,  Haiyu Zhou2*
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1 School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
2 Department of Thoracic Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
3 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China
4 Department of Thoracic Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
5 Department of General Practice, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
6 The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
7 School of Chinese Medicine, Faculty of Medicine, Macao University of Science and Technology, Macao, China
BMT, 173 https://doi.org/10.12336/bmt.25.00173
Submitted: 6 September 2025 | Revised: 9 November 2025 | Accepted: 18 November 2025 | Published: 23 February 2026
© 2026 by the Author(s). Licensee Biomaterials Translational, USA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 (CC BY-NC-SA 4.0) (https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en)
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Abstract

Hyperactivation of the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT) pathway, a key downstream effector of the epidermal growth factor receptor (EGFR), drives resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma by promoting cell proliferation and metastasis, often compounded by compensatory pathway activation. Integrated analysis of Gene Expression Omnibus datasets confirmed PI3K/AKT hyperactivation in resistant tumors. Drug synergy analysis revealed a potent interaction between gefitinib and crizotinib (Crz). Mechanistic studies using phospho-proteomics showed that Crz co-treatment synergistically suppresses both PI3K/AKT and compensatory extracellular signal-regulated protein kinases activation, significantly inhibiting the proliferation and invasion of PC-9 gefitinib-resistant cells. In vivo validation using xenografts and zebrafish metastasis models demonstrated that this combination strategy overcomes drug resistance and inhibits metastasis. To optimize pharmacokinetic coordination and efficacy, dual drug-loaded poly (ethylene glycol)–poly (hexyl ethylene phosphate) nanoparticles with high loading capacity were engineered. In this multiscale study, we established rationally designed nanocarriers for a dual-pathway blockade as a transformative strategy against TKI resistance, providing a clinically translatable platform for overcoming metastatic progression.

Keywords
Lung adenocarcinoma
Gefitinib resistance
Crizotinib
Phosphatidylinositol 3-kinase–protein kinase B signaling
Nanoparticles
Funding
This work was supported by the National Natural Science Foundation of China (82472064), the International Science and Technology Cooperation Program of Guangdong (2022A0505050048), the Natural Science Foundation of Guangdong (2024A1515012369), and the Beijing Xisike Clinical Oncology Research Foundation (Y-HS202102-0038).
Conflict of interest
The authors declare no conflicts of interest.
References
  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi: 10.3322/caac.21708

 

  1. Bender E. Epidemiology: The dominant malignancy. Nature. 2014;513(7517):S2-S3. doi: 10.1038/513S2a

 

  1. Shah MP, Neal JW. Targeting acquired and intrinsic resistance mechanisms in epidermal growth factor receptor mutant non-small-cell lung cancer. Drugs. 2022;82(6):649-662. doi: 10.1007/s40265-022-01698-z

 

  1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 2013;13(10):714-726. doi: 10.1038/nrc3599

 

  1. Yu W, Ye F, Yuan X, et al. A phase I/II clinical trial on the efficacy and safety of NKT cells combined with gefitinib for advanced EGFR-mutated non-small-cell lung cancer. BMC Cancer. 2021;21(1):877. doi: 10.1186/s12885-021-08590-1

 

  1. Han W, Shi L, Ren L, et al. A nanomedicine approach enables co-delivery of cyclosporin A and gefitinib to potentiate the therapeutic efficacy in drug-resistant lung cancer. Signal Transduct Target Ther. 2018;3:16. doi: 10.1038/s41392-018-0019-4

 

  1. Zhao L, Yang G, Shi YJ, Su C, Chang J. Co-delivery of Gefitinib and chloroquine by chitosan nanoparticles for overcoming the drug acquired resistance. J Nanobiotechnology. 2015;13:57. doi: 10.1186/s12951-015-0121-5

 

  1. Liu Y, Dai X, Jiang S, et al. Targeted co-delivery of gefitinib and rapamycin by aptamer-modified nanoparticles overcomes EGFR-TKI resistance in NSCLC via promoting autophagy. Int J Mol Sci. 2022;23(14):8025. doi: 10.3390/ijms23148025

 

  1. Wu Y, Cheng Y, Zhou J, et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): An open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020;8(11):1132-1143. doi: 10.1016/S2213-2600(20)30154-5

 

  1. Li S, Zeng F, Zhou Q, et al. NIR-II photoacoustic imaging-guided chemo-photothermal therapy using PA1094T combined with anti-CD47 antibody: Activating pyroptosis against orthotopic glioblastoma. Adv Healthc Mater. 2025;14(3):e2403108. doi: 10.1002/adhm.202403108

 

  1. Xu B, Zeng F, Deng J, et al. A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy. Bioact Mater. 2023;27:337-347. doi: 10.1016/j.bioactmat.2023.04.005

 

  1. Qu J, Li J, Zhang Y, et al. AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway. Cell Biosci. 2021;11(1):163. doi: 10.1186/s13578-021-00677-3

 

  1. Si X, Xu F, Xu F, Wei M, Ge Y, Chenge S. CADM1 inhibits ovarian cancer cell proliferation and migration by potentially regulating the PI3K/Akt/mTOR pathway. Biomed Pharmacother. 2020;123:109717. doi: 10.1016/j.biopha.2019.109717

 

  1. Hu C, Zha Q, Hua P, Xiao L, Pan D. NUCKS promotes the proliferation, migration and invasion of lung cancer cells through Pi3k/Akt signaling pathway. Clin Invest Med. 2021;44(2):E55-E61. doi: 10.25011/cim.v44i2.36246

 

  1. Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol. 2022;85:69-94. doi: 10.1016/j.semcancer.2021.06.019

 

  1. Hao J, Zhang W, Huang Z. Bupivacaine modulates the apoptosis and ferroptosis in bladder cancer via phosphatidylinositol 3-kinase (PI3K)/ AKT pathway. Bioengineered. 2022;13(3):6794-6806. doi: 10.1080/21655979.2022.2036909

 

  1. Gao H, Wang W, Li Q. GANT61 suppresses cell survival, invasion and epithelial-mesenchymal transition through inactivating AKT/mTOR and JAK/STAT3 pathways in anaplastic thyroid carcinoma. Cancer Biol Ther. 2022;23(1):369-377. doi: 10.1080/15384047.2022.2051158

 

  1. Ding J, Ding X, Leng Z. LPCAT1 promotes gefitinib resistance via upregulation of the EGFR/PI3K/AKT signaling pathway in lung adenocarcinoma. J Cancer. 2022;13(6):1837-1847. doi: 10.7150/jca.66126

 

  1. Deng Q, Fang Q, Ji X, Zhou S. Cyclooxygenase-2 mediates Gefitinib resistance in non-small cell lung cancer through the EGFR/PI3K/AKT axis. J Cancer. 2020;11(12):3667-3674. doi: 10.7150/jca.42850

 

  1. Zaryouh H, De Pauw I, Baysal H, et al. Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma. Med Res Rev. 2022;42(1):112-155. doi: 10.1002/med.21806

 

  1. Sato H, Yamamoto H, Sakaguchi M, et al. Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Cancer Sci. 2018;109(10):3183-3196. doi: 10.1111/cas.13763

 

  1. Wei C, Dong X, Lu H, et al. LPCAT1 promotes brain metastasis of lung adenocarcinoma by up-regulating PI3K/AKT/MYC pathway. J Exp Clin Cancer Res. 2019;38(1):95. doi: 10.1186/s13046-019-1092-4

 

  1. Zhu L, Yang F, Wang G, Li Q. CXC motif chemokine receptor type 4 disrupts blood-brain barrier and promotes brain metastasis through activation of the PI3K/AKT pathway in lung cancer. World Neurosurg. 2022;166:e369-e381. doi: 10.1016/j.wneu.2022.07.005

 

  1. Li Q, Yang J, Yu Q, et al. Associations between single-nucleotide polymorphisms in the PI3K-PTEN-AKT-mTOR pathway and increased risk of brain metastasis in patients with non-small cell lung cancer. Clin Cancer Res. 2013;19(22):6252-6260. doi: 10.1158/1078-0432.CCR-13-1093

 

  1. Park S, Cho EA, Chun JN, et al. Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells. Exp Mol Med. 2022;54(8):1225-1235. doi: 10.1038/s12276-022-00835-8

 

  1. Xu W, Kim JW, Jung WJ, Koh Y, Yoon SS. Crizotinib in combination with everolimus synergistically inhibits proliferation of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res Treat. 2018;50(2):599-613. doi: 10.4143/crt.2016.357

 

  1. Megiorni F, McDowell HP, Camero S, et al. Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition. J Exp Clin Cancer Res. 2015;34:112. doi: 10.1186/s13046-015-0228-4

 

  1. Wang X, Cao J, Du W, Zhang W, Cao S. Response to gefitinib/ crizotinib combination in a pulmonary sarcomatoid carcinoma patient harboring concurrent EGFR mutation and MET amplification. Clin Case Rep. 2021;9(7):e04487. doi: 10.1002/ccr3.4487

 

  1. Li D, Wang J, Ma Y, et al. A donor-acceptor conjugated polymer with alternating isoindigo derivative and bithiophene units for near-infrared modulated cancer thermo-chemotherapy. ACS Appl Mater Interfaces. 2016;8(30):19312-19320. doi: 10.1021/acsami.6b05495

 

  1. Shou J, You L, Yao J, et al. Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3. Cancer Lett. 2016;379(1):124-133. doi: 10.1016/j.canlet.2016.06.002

 

  1. Tehranian C, Fankhauser L, Harter PN, et al. The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis. Neuro Oncol. 2022;24(2):213-225. doi: 10.1093/neuonc/noab159

 

  1. Jiang B, Mu Q, Qiu F, et al. Machine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors. Nat Commun. 2021;12(1):6692. doi: 10.1038/s41467-021-27017-w

 

  1. Hu Y, Zhao Z, Harmon T, Pentel PR, Ehrich M, Zhang C. Paradox of PEGylation in fabricating hybrid nanoparticle-based nicotine vaccines. Biomaterials. 2018;182:72-81. doi: 10.1016/j.biomaterials.2018.08.015

 

  1. Zhu Y, Chen C, Cao Z, et al. On-demand PEGylation and dePEGylation of PLA-based nanocarriers via amphiphilic mPEG-TK-Ce6 for nanoenabled cancer chemotherapy. Theranostics. 2019;9(26):8312-8320. doi: 10.7150/thno.37128

 

  1. Pretor S, Bartels J, Lorenz T, et al. Cellular uptake of coumarin-6 under microfluidic conditions into HCE-T cells from nanoscale formulations. Mol Pharm. 2015;12(1):34-45. doi: 10.1021/mp500401t

 

  1. Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138. doi: 10.1186/s12943-023-01827-6

 

  1. Wei Q, Li P, Yang T, et al. The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors. J Hematol Oncol. 2024;17(1):1. doi: 10.1186/s13045-023-01509-2

 

  1. Manzari MT, Shamay Y, Kiguchi H, Rosen N, Scaltriti M, Heller DA. Targeted drug delivery strategies for precision medicines. Nat Rev Mater. 2021;6(4):351-370. doi: 10.1038/s41578-020-00269-6

 

  1. Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17(1):53. doi: 10.1186/s12943-018-0793-1

 

  1. Fang W, Huang Y, Gu W, et al. PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy. Transl Lung Cancer Res. 2020;9(4):1258-1267. doi: 10.21037/tlcr-20-141

 

  1. Moore NF, Azarova AM, Bhatnagar N, et al. Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget. 2014;5(18):8737-8749. doi: 10.18632/oncotarget.2372

 

  1. Yan H, Jung K, Son M, et al. Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer. Oncotarget. 2014;5(19):9150-9168. doi: 10.18632/oncotarget.2363

 

  1. Liu L, Qu J, Heng J, et al. A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant non-small-cell lung cancer after development of EGFR-TKI resistance. Front Oncol. 2021;11:722039. doi: 10.3389/fonc.2021.722039

 

  1. Dinavahi SS, Noory MA, Gowda R, et al. Moving synergistically acting drug combinations to the clinic by comparing sequential versus simultaneous drug administrations. Mol Pharmacol. 2018;93(3):190-196. doi: 10.1124/mol.117.110759
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