Anti-EGFR Antibody-Drug Conjugate Carrying an Inhibitor Targeting CDK Restricts Triple-Negative Breast Cancer Growth

被引:11
作者
Cheung, Anthony [1 ,2 ]
Chenoweth, Alicia M. [1 ,2 ]
Johansson, Annelie [1 ,3 ]
Laddach, Roman [2 ,4 ]
Guppy, Naomi [5 ]
Trendell, Jennifer [1 ]
Esapa, Benjamina [2 ]
Mavousian, Antranik [5 ]
Navarro-Llinas, Blanca [1 ]
Haider, Syed [5 ]
Romero-Clavijo, Pablo [2 ]
Hoffmann, Ricarda M. [2 ,5 ]
Andriollo, Paolo [6 ]
Rahman, Khondaker M. [6 ]
Jackson, Paul [6 ]
Tsoka, Sophia [4 ]
Irshad, Sheeba [1 ]
Roxanis, Ioannis [5 ]
Grigoriadis, Anita [1 ,3 ]
Thurston, David E. [6 ]
Lord, Christopher J. [5 ]
Tutt, Andrew N. J. [1 ,5 ]
Karagiannis, Sophia N. [1 ,2 ]
机构
[1] Kings Coll London, Guys Canc Ctr, Sch Canc & Pharmaceut Sci, Breast Canc Now Res Unit, Tower Wing,9th Floor, London SE1 9RT, England
[2] Kings Coll London, Guys Hosp, Sch Basic & Med Biosci, St Johns Inst Dermatol, Tower Wing,9th Floor, London SE1 9RT, England
[3] Kings Coll London, Guys Canc Ctr, Sch Canc & Pharmaceut Sci, Canc Bioinformat, London, England
[4] Kings Coll London, Fac Nat Math & Engn Sci, Dept Informat, London, England
[5] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England
[6] Kings Coll London, Sch Canc & Pharmaceut Sci, Inst Pharmaceut Sci, London, England
基金
英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
SACITUZUMAB GOVITECAN; PHASE-II; CHEMOTHERAPY; IDENTIFICATION; ARCHITECTURE; RESISTANCE; CETUXIMAB; REVEALS; DIVERSE;
D O I
10.1158/1078-0432.CCR-23-3110
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-na & iuml;ve 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.
引用
收藏
页码:3298 / 3315
页数:18
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