Anti-EGFR Antibody-Drug Conjugate Carrying an Inhibitor Targeting CDK Restricts Triple-Negative Breast Cancer Growth.
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ICR Authors
Authors
Cheung, A
Chenoweth, AM
Johansson, A
Laddach, R
Guppy, N
Trendell, J
Esapa, B
Mavousian, A
Navarro-Llinas, B
Haider, S
Romero-Clavijo, P
Hoffmann, RM
Andriollo, P
Rahman, KM
Jackson, P
Tsoka, S
Irshad, S
Roxanis, I
Grigoriadis, A
Thurston, DE
Lord, CJ
Tutt, ANJ
Karagiannis, SN
Chenoweth, AM
Johansson, A
Laddach, R
Guppy, N
Trendell, J
Esapa, B
Mavousian, A
Navarro-Llinas, B
Haider, S
Romero-Clavijo, P
Hoffmann, RM
Andriollo, P
Rahman, KM
Jackson, P
Tsoka, S
Irshad, S
Roxanis, I
Grigoriadis, A
Thurston, DE
Lord, CJ
Tutt, ANJ
Karagiannis, SN
Document Type
Journal Article
Date
2024-08-01
Date Accepted
2024-05-15
Abstract
PURPOSE: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. EXPERIMENTAL DESIGN: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. RESULTS: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. CONCLUSIONS: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.
Citation
Clinical Cancer Research, 2024, 30 (15), pp. 3298 - 3315
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
1557-3265
1557-3265
Collections
Research Team
Gene Function
Directorate Breast Canc
Directorate Breast Canc