Editor's Note: The 47th San Antonio Breast Cancer Symposium (SABCS) recently concluded successfully in San Antonio, USA. SABCS is the world’s largest conference in the field of breast cancer, attracting more than 10,000 registered participants from 102 countries. Over four days, the conference featured thousands of keynote speeches and research abstracts. On December 11, during the second day of the conference, Nobel Laureate in Physiology or Medicine (2019) Professor William Kaelin delivered a highly acclaimed keynote address on the topic of "Tumor Genetics and Targeted Drug Development." Oncology Frontier had the privilege of interviewing Dr. Guojun Zhang from Yunnan Cancer Hospital for a comprehensive review and summary of this lecture.

Oncology Frontier: The 2024 SABCS conference presented numerous research advancements in breast cancer. Which report particularly caught your attention, and how might it impact drug development and clinical treatment for breast cancer and other tumors?

Dr. Guojun Zhang: What stood out to me was the keynote address delivered by Professor William Kaelin on the morning of December 11. His lecture on “Tumor Genetics and Targeted Drug Development” was highly insightful and holds significant value for both basic researchers and new drug developers.

Professor Kaelin emphasized four critical points in his lecture.

First, he highlighted the importance of establishing causal relationships between events. Using the analogy between his career and stock market performance, he introduced the concept of causality. He explained how the rapid growth of tumors, the onset of hypoxia, and the increase in hypoxia-inducible factors (HIF) are causally linked. Hypoxia not only elevates HIF levels but also accelerates tumor growth. Determining causal relationships is vital. For instance, identifying a target gene and observing subsequent phenotypic changes in tumors after altering this gene confirms causality. However, many gene alterations are merely correlated with disease prognosis, which does not necessarily make them suitable drug targets. A classic example is the correlation between ventilator use in ICU patients with lung disease and poor prognosis. Ventilator use is more common in critically ill patients, leading to worse outcomes, but the device itself is not the cause of poor prognosis.

Second, Professor Kaelin discussed how to identify suitable drug targets during drug development. He shared various methodologies, including gene editing, drug inhibition, and animal models, which are instrumental in clarifying gene functions and pinpointing effective therapeutic targets.

Third, he emphasized combination therapy. Combining drugs is a crucial strategy to overcome resistance, especially cross-resistance. A 1 cm tumor contains approximately 1 billion cancer cells. Single-drug treatments, even if only one in a million cells survives, can lead to resistance. Using three drugs with different mechanisms of action can nearly eradicate all tumor cells. However, if these drugs share similar mechanisms, cross-resistance may still occur. Therefore, selecting drugs with distinct mechanisms is essential for effective combination therapy.

Fourth, he addressed how to turn “undruggable” proteins into viable therapeutic targets. While some proteins, like tyrosine kinases, can be inhibited by specific drugs, others cannot be directly suppressed and require targeted degradation. This transforms previously undruggable proteins into actionable targets. For a protein to be considered a promising drug target, two criteria must be met: altering the target must change the tumor phenotype (genetic validation), and modulating the target must biologically suppress tumor growth. Established targets such as BRAF, HER2, and EGFR not only pass genetic validation but also exhibit biological plausibility. Therefore, foundational research should focus on identifying and validating actionable targets, avoiding the misconception that genes merely correlated with prognosis can automatically become therapeutic targets.

Additionally, Professor Kaelin elaborated on the concept of synthetic lethality, which occurs when inhibiting a secondary gene causes tumor cell death in the presence of an existing genetic abnormality, while normal cells remain unaffected. A classic example is the use of PARP inhibitors in triple-negative breast cancer patients with BRCA1/2 mutations, yielding significant therapeutic benefits. PARP inhibitors are now widely used in treating BRCA-mutated breast cancers. However, challenges arise when developing drugs based on this principle. For example, inhibiting gene B in the presence of a mutation in gene A may kill tumor cells, but gene B might have compensatory mechanisms (B1, B2, B3). In this case, inhibiting only B1 is ineffective; simultaneous inhibition of B1, B2, and B3 is required, complicating drug development. Overcoming this challenge will be crucial for bringing more effective targeted therapies into clinical use.

Dr. Guojun Zhang

• MD, PhD, Professor, Chief Physician, Doctoral Supervisor
• President, Yunnan Cancer Hospital (Beijing Cancer Hospital Yunnan Hospital, Third Affiliated Hospital of Kunming Medical University)
• Director, Fujian Provincial Key Laboratory of Precision Diagnosis and Treatment of Breast Cancer
• Director, Xiamen Key Laboratory of Precision Diagnosis and Treatment of Endocrine Tumors
• Director, Xiamen Clinical Medical Research Center for Breast and Thyroid Tumors
• Distinguished Professor, Changjiang Scholars Program
• Distinguished Talent, National High-Level Talent Special Support Program (Ten Thousand Talents Program)
• National-Level Candidate, New Century National Talent Project
• Class A High-Level Talent, Fujian Province
• Innovative Talent, Fujian “Hundred Talents Plan”
• Distinguished Talent, Guangdong Special Support Program
• Vice President, Environmental Medicine Branch, Chinese Research Hospital Association
• Council Member, Chinese Anti-Cancer Association; Deputy Chair, International Medical Exchange Branch; Standing Member, Integrated Oncology Branch
• Standing Member, Chinese Medical Doctor Association Oncology Physicians Branch
• Standing Member, Second Committee, Oncology Physicians Branch, Chinese Medical Doctor Association