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PROTAC-mediated structure-function disruption of CD26: a therapeutic strategy for driver-negative non-small cell lung
Guangjian Zhang1, Bohao Liu1, Deqian Qiao2
1Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Enhanced Recovery After Surgery of Integrated Chinese and Western Medicine, Administration of Traditional Chinese Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
Background:
Previous targeted therapies for non-small cell lung cancer (NSCLC) have focused on targeting driver mutations (e.g., EGFR/ALK), leading to approximately 30-40% of patients with negative mutations lacking effective treatments. Therefore, there is an urgent need for innovative therapeutic strategies for these patients.
Methods:
CD26-targeted proteolysis-targeting chimeras (PROTACs: P4-1 to P4-4) were designed and synthesised. The binding strengths between degraders and CD26 were evaluated through surface plasmon resonance (SPR). The ternary complex formations were confirmed by NanoBRET™ live-cell ternary complex profiling assay. Driver-negative NSCLC (NCI-H460 and NCI-H1299) and BEAS-2B cells were used to study the degradation performances of degraders. The therapeutic efficacies of the optimal degrader (P4-3) were assessed via cell line-derived xenografts (CDX), in situ lung cancer and patient-derived organoids (PDOs) models. Mechanistic studies incorporated co-immunoprecipitation, immunofluorescence, reactive oxygen species (ROS)/DNA damage detection, apoptosis assays and transcriptomics.
Findings:
CD26 underwent clathrin-dependent endocytosis induced by P4-3 and ternary complex were formed before protein degradation. Degradation of CD26 by P4-3 resulted in the cytoplasmic translocation of membrane-bound adenosine deaminase (ADA), leading to adenosine depletion, mitochondrial ROS accumulation, metabolic stress, DNA damage, and intrinsic apoptosis in vitro, in vivo and in PDOs (negative mutations) models. Mechanistically, degradation of CD26 uniquely eliminates both its enzymatic activity and non-enzymatic functions, achieving a dual effect unattainable with conventional inhibitors.
Interpretation:
Targeted CD26 degradation represents a valuable therapeutic strategy for driver-negative NSCLC. And this approach also addresses the limitations of driver mutation-targeted based therapies, providing a promising method for NSCLC patients with negative mutations.
Funding:
This study was funded by the Key Research and Development Project of Shaanxi Province (2023-YBSF-292), the opening foundation (M2022-3) from Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, Ministry of Education, Qingdao University of Science and Technology, the National Natural Science Foundation of China (82102976, 52203337), the Youth Top Talent Program (11301223010722) from Xi'an Jiaotong University, the Key Research and Development Project of Shaanxi Province (2024SF-ZDCYL-02-09) and Capacity Improvement Plan of Shaanxi Health Committee (2024PT-09).
Insights
Targeted CD26 degradation offers a new therapeutic strategy for non-small cell lung cancer (NSCLC) patients lacking driver mutations. This proteolysis-targeting chimera (PROTAC) approach degrades CD26, inducing cancer cell death and overcoming limitations of current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Many non-small cell lung cancer (NSCLC) patients lack actionable driver mutations, necessitating novel treatment strategies.
- Existing targeted therapies primarily focus on mutations like EGFR/ALK, leaving a significant patient subset underserved.
Purpose of the Study:
- To design and evaluate CD26-targeted proteolysis-targeting chimeras (PROTACs) as a novel therapeutic approach for driver-negative NSCLC.
- To investigate the mechanism of action and therapeutic efficacy of CD26 degradation in preclinical NSCLC models.
Main Methods:
- Synthesis and characterization of novel CD26-targeted PROTACs (P4-1 to P4-4).
- Evaluation of PROTAC binding affinity (SPR) and ternary complex formation (NanoBRET™).
- Assessment of degradation efficacy in driver-negative NSCLC cell lines, xenografts, and patient-derived organoids.
Main Results:
- The optimal PROTAC, P4-3, induced CD26 degradation via clathrin-dependent endocytosis.
- CD26 degradation led to adenosine depletion, ROS accumulation, DNA damage, and apoptosis in vitro and in vivo.
- Degradation of CD26 exhibited dual effects, eliminating both enzymatic and non-enzymatic functions.
Conclusions:
- Targeted CD26 degradation is a promising therapeutic strategy for driver-negative NSCLC.
- This approach overcomes limitations of current mutation-targeted therapies, offering hope for patients with limited options.
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