Editor’s Note

The 2025 European Society for Medical Oncology (ESMO) Annual Congress, held in Berlin, Germany from October 17 to 21, brought together global experts to present cutting-edge advances in cancer research — from basic science to translational breakthroughs and clinical innovation.

Among the featured presentations, a study by Prof. Man Li’s team from The Second Hospital of Dalian Medical University was selected as an e-poster (Abstract #61eP) for inclusion in the poster exhibition. The work focuses on the molecular mechanisms of drug resistance in HER2-positive breast cancer, particularly the co-amplification of CDK12 and ERBB2, revealing new insights into the link between metabolic regulation, DNA repair, and therapeutic resistance. The study highlights the team’s continued excellence in molecular oncology and translational research.

Study Overview

Background

Cyclin-dependent kinase 12 (CDK12) is a key cell cycle–related kinase involved in DNA damage response and transcriptional regulation. In HER2-positive breast cancer, CDK12 is frequently co-amplified with ERBB2. Previous research has primarily focused on the role of CDK12 in regulating homologous recombination repair (HRR); however, whether CDK12 also influences DNA repair capacity through mitochondrial metabolic pathways remains unclear.

Key Findings at a Glance:

• CDK12 and ERBB2 co-amplification occurs frequently and is closely associated with poor prognosis in HER2-positive breast cancer.

• Early evidence suggests that CDK12 may activate mitochondrial oxidative phosphorylation (OXPHOS), thereby enhancing HRR activity and influencing the tumor’s response to DNA damage–inducing therapies.

• Inhibition of OXPHOS partially reversed CDK12-mediated HRR enhancement and chemotherapy resistance, indicating that metabolic reprogramming may play a central role in regulating DNA repair capacity.

Methods

Using next-generation sequencing (NGS) data from the team’s institutional breast cancer cohort and multiple publicly available datasets, the study systematically analyzed the distribution patterns of CDK12 and ERBB2 co-amplification.

In HER2-positive breast cancer cell models, the researchers performed CDK12 knockdown, overexpression, and pharmacologic intervention experiments. These were coupled with metabolic profiling and DNA repair activity assays to explore CDK12’s involvement in OXPHOS and HRR processes.

Results

The study focused on uncovering the functional consequences of CDK12-related alterations in HER2-positive breast cancer. Preliminary data indicated that CDK12 may enhance tumor cell DNA repair capacity by regulating mitochondrial metabolism, thus affecting responsiveness to DNA-damaging chemotherapies.

Importantly, the team discovered that targeting specific metabolic pathways could weaken the CDK12-driven enhancement of DNA repair, suggesting that CDK12 acts as a molecular bridge linking metabolism, DNA repair, and chemoresistance. This finding opens new directions for understanding resistance mechanisms in HER2-positive breast cancer.

Investigator’s Commentary

“Breast cancer remains one of the most prevalent malignancies among women, and molecular subtyping is crucial for guiding treatment strategies,” said Prof. Man Li, Director of Oncology at The Second Hospital of Dalian Medical University.

“In HER2-positive breast cancer, combining targeted therapy with chemotherapy has significantly improved outcomes. However, due to the substantial molecular heterogeneity within this subtype, not all patients derive the same degree of benefit. Understanding the underlying biological diversity is therefore key to identifying new therapeutic targets.”

“Although CDK12–ERBB2 co-amplification has been reported previously, its unique biological effects and mechanistic implications have not been fully characterized. Our study suggests that CDK12’s role extends beyond transcriptional regulation and homologous recombination. By focusing on mitochondrial metabolism, we propose a potential CDK12–OXPHOS–HRR axis, outlining a new ‘metabolism–repair’ cascade that may underpin treatment resistance.”

“This concept not only expands our understanding of CDK12’s functional landscape but also offers a new therapeutic entry point for overcoming resistance in HER2-positive breast cancer. The ‘metabolism–repair–resistance’ model we propose provides both a theoretical framework for future mechanistic studies and a rationale for the development of combined metabolic and DNA repair–targeted strategies in clinical practice.”

Prof. Man Li, MD, PhD

Professor and Doctoral Supervisor Director, Department and Division of Oncology The Second Hospital of Dalian Medical University

Dr. Qiping Zhuo

PhD Candidate in Oncology, Dalian Medical University