Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth

  • Clin Cancer Res. 2024 May 21. doi: 10.1158/1078-0432.CCR-23-3110.
Anthony Cheung  1 ,  Alicia M Chenoweth  1 ,  Annelie Johansson  1 ,  Roman Laddach  1 ,  Naomi Guppy  2 ,  Jennifer Trendell  1 ,  Benjamina Esapa  1 ,  Antranik Mavousian  2 ,  Blanca Navarro-Llinas  1 ,  Syed Haider  2 ,  Pablo Romero-Clavijo  1 ,  Ricarda M Hoffmann  2 ,  Paolo Andriollo  3 ,  Khondaker Miraz Rahman  1 ,  Paul Jackson  3 ,  Sophia Tsoka  1 ,  Sheeba Irshad  1 ,  Ioannis Roxanis  2 ,  Anita Grigoriadis  1 ,  David E Thurston  4 ,  Christopher J Lord  2 ,  Andrew N J Tutt  5 ,  Sophia N Karagiannis  1
Affiliations
  • 1. King's College London, London, United Kingdom.
  • 2. Institute of Cancer Research, London, United Kingdom.
  • 3. King's College London, United Kingdom.
  • 4. King's College London.
  • 5. The Institute of Cancer Research London, London, United Kingdom.
PMID: 38772416 DOI: 10.1158/1078-0432.CCR-23-3110
Abstract

Purpose: Anti-EGFR antibodies show limited response in breast Cancer, partly due to activation of compensatory pathways. Furthermore, despite clinical success of CDK4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBCs) are largely resistant due to CDK2/cyclin E expression, while 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: Expression 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 anti-tumor functions in vitro and in orthotopically-grown basal-like/TNBC xenografts.

Results: Transcriptomic (6173 primary, 27 baseline and matched post-chemotherapy residual tumors), scRNA-seq (150290 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 fraction of the drug, 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.

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