Triple-negative breast cancer (TNBC) is known for its aggressiveness and poor prognosis, primarily due to the lack of hormone receptor expression and HER2 amplification. Among the TNBC subtypes, the luminal androgen receptor (LAR) subtype stands out for its distinct clinical features, including low proliferation rates but high metastatic potential, making it less responsive to conventional therapies. Recent genomic analyses have identified actionable mutations in ERBB2, which are largely confined to the LAR subtype. Despite this discovery, treatment options remain limited, prompting a deeper investigation into the molecular drivers of LAR TNBC. These challenges underline the need for comprehensive therapeutic strategies addressing both genetic and tumor microenvironmental factors.
Researchers from Fudan University Shanghai Cancer Center, in their 2026 publication in Cancer Biology & Medicine, have identified key therapeutic vulnerabilities in the LAR subtype of TNBC. Their study, published (DOI: 10.20892/j.issn.2095-3941.2025.0691) on March 2026, demonstrates that ERBB2 mutations, which activate the HER2 signaling pathway, and a senescence-driven immune suppression mechanism, both contribute to the malignancy's resistance to conventional therapies. These findings open doors for innovative treatment strategies combining targeted inhibition of ERBB2 and immunotherapy, particularly for patients with high senescence scores.
The study utilized comprehensive multi-omic approaches, including whole-exome sequencing and RNA sequencing, to uncover the molecular landscape of the LAR subtype in TNBC. A striking feature of this subtype is the high frequency of somatic mutations in ERBB2, specifically in its kinase domain, including variants like V777L and E698_P699delinsA, which confer sensitivity to tyrosine kinase inhibitors (TKIs) like neratinib. The study further explored the transcriptomic profile of LAR tumors, revealing that cellular senescence plays a dominant role in shaping the tumor microenvironment. The senescence-associated secretory phenotype (SASP) was found to promote immune suppression, contributing to resistance to immunotherapy. Machine learning models developed in the study, incorporating senescence-associated genes, were able to predict relapse-free survival and identify patients who would benefit from a combination of senescence-targeted therapy and immunotherapy. These findings position ERBB2 mutations and cellular senescence as dual therapeutic targets for LAR TNBC, suggesting the need for clinical trials to explore these combined approaches.
"The findings from this study highlight critical vulnerabilities in the LAR subtype of TNBC," said Dr. Zhiming Shao, the corresponding author of the study. "By targeting both the ERBB2 mutations and the senescence-associated immune suppression, we can potentially improve patient outcomes, particularly those resistant to conventional therapies. These dual-target strategies open up exciting opportunities for future clinical trials, combining targeted therapies with immunotherapy to provide a more personalized and effective treatment for patients with this aggressive cancer subtype."
The identification of ERBB2 mutations and senescence as key drivers of LAR TNBC has important implications for treatment strategies. Targeting ERBB2 mutations with next-generation TKIs like neratinib, combined with therapies modulating cellular senescence, could provide a dual approach to overcome chemoresistance and improve patient survival. Furthermore, the LAR-S signature developed in this study offers a robust tool for predicting patient prognosis and guiding therapeutic decisions. These insights could pave the way for clinical trials that test combination therapies, ultimately improving the management of LAR TNBC and offering new hope for patients with this difficult-to-treat cancer subtype.
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References
DOI
10.20892/j.issn.2095-3941.2025.0691
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0691
Funding information
This work received funding from the Ministry of Science and Technology of China (Grant Nos. 2023YFF1205003, 2023YFF0613304, and 2023YFC3402504), the National Key R&D Program of China (Grant No. 2023YFF0613300, 2023YFF1205003), and the National Natural Science Foundation of China (Grant Nos. 82473499, 82272957, and 82303735).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).