Breaking Resistance, Shaping the Future | Research Voices (Episode 5) - Prof. Naoto T. Ueno, University of Hawaiʻi Cancer Center

Prof. Naoto T. Ueno Reflects on ADC Resistance, TME Heterogeneity, and Next-Generation Combination Therapies in Breast Cancer

As part of Breaking Resistance, Shaping the Future, a scientific series celebrating the eighth anniversary of Cancer Drug Resistance (CDR), the journal is pleased to present the latest episode of Research Voices, an interview series spotlighting leading scientific experts and clinical pioneers from around the world.

This episode features Professor Naoto T. Ueno, a globally recognized authority in translational breast cancer research and Director of the University of Hawaiʻi Cancer Center.

In this engaging conversation, Prof. Ueno discusses the rapidly evolving landscape of antibody-drug conjugates (ADCs) in solid tumors, focusing particularly on Sacituzumab Govitecan and combination regimens evaluated in landmark clinical trials like ASCENT-04. He provides deep mechanistic insights into the intricate dynamics of the tumor microenvironment (TME) - highlighting how cancer-associated fibroblasts, endothelial alterations, T-cell enrichment, and lymphocytic infiltration govern therapeutic response. Furthermore, Prof. Ueno explores the clinical hurdles in defining TME heterogeneity, the potential of bispecific ADCs and PROTACs, and the critical role of translational platforms such as patient-derived organoids (PDOs), PDX models, and microfluidic chips in establishing tailored, longitudinal strategies to overcome resistance.

Watch the Full Interview

Interview Highlights

• Mechanisms of ADC resistance and combination strategies with PD-1/PD-L1 inhibitors like pembrolizumab
• Insights from phase 3 clinical trials, including ASCENT-04 in triple-negative breast cancer (TNBC)
• The role of TME components - such as cancer-associated fibroblasts and tumor-infiltrating lymphocytes - in shaping drug response
• Overcoming the challenges of defining dynamic TME heterogeneity through longitudinal data
• The therapeutic potential of bispecific ADCs, dual-targeting agents, and PROTACs
• Utilizing patient-derived organoids, PDX models, and microfluidic chips for personalized precision medicine

Key Takeaways

Navigating ADC Resistance and Combination Regimens

Prof. Ueno discusses the clinical performance and resistance mechanisms associated with ADCs in breast cancer, particularly Sacituzumab Govitecan. He notes that while single-agent ADCs demonstrate significant clinical benefit, comparing response rates between ADC monotherapy and combinations with immune checkpoint inhibitors (such as pembrolizumab in patients with high PD-L1 expression) is essential for improving durable outcomes. He emphasizes that understanding primary and acquired resistance in trials like ASCENT-04 is key to designing smarter, rational combination protocols.

Unraveling TME Heterogeneity and Longitudinal Dynamics

The conversation touches upon the profound complexity of the tumor microenvironment. Prof. Ueno highlights that TME is not a static entity; components like cancer-associated fibroblasts, endothelial changes, T-cell enrichment, and lymphocytic infiltration dynamically interact with therapies. Because TME varies across patient cohorts and evolves over time, he stresses the critical need for longitudinal data to track these spatial and temporal alterations, acknowledging that defining a universal TME biomarker remains an ongoing challenge in precision oncology.

Innovating Preclinical Platforms for Tailored Therapeutics

Prof. Ueno reflects on the future of targeted and cell-degrading modalities, including bispecific ADCs, dual-targeting molecules, and PROTACs. To effectively evaluate these novel drugs, he underscores the necessity of moving beyond traditional 2D cell cultures toward sophisticated translational models. By leveraging patient-derived organoids (PDOs), PDX mouse models, and microfluidic chips, researchers can better recapitulate human physiological fluidics and TME interactions, ultimately paving the way for a much more tailored and effective approach to overcoming cancer drug resistance.

This interview marks a key installment of the Research Voices series. Stay tuned for upcoming conversations with leading experts as we continue to explore the theme Breaking Resistance, Shaping the Future.

Editor: Stella Jin
Language Editor: Amir Khan
Production Editor: Xingyue Luo
Respectfully Submitted by the Editorial Office of Cancer Drug Resistance