Development of HER2 Heterogeneous Breast Cancer Models, Presenting New Therapeutic Strategies
In cancer research, intratumor heterogeneity of HER2-positive breast cancer is a major cause of resistance to HER2-targeted therapies. The lack of preclinical models that can accurately model this internal heterogeneity has hindered the development of treatments for HER2 heterogeneous tumors. Recently, a human HER2 heterogeneous breast cancer model was developed, consisting of ERBB2-amplified (HER2hi) and non-amplified (HER2lo) cell populations derived from the same tumor. Using these models and cellular barcoding, the researchers demonstrated subclonal cooperation between HER2hi and HER2lo subpopulations. Additionally, HER2lo cells were found to induce resistance to HER2-targeting antibody-drug conjugates (ADCs) such as T-DXd, but were sensitive to HER2 kinase inhibitors. CRISPR screens identified ABCC1 and USP9X as factors that sensitize HER2lo cells to T-DXd in heterogeneous co-cultures. Inhibition of USP9X enhanced the lysosomal targeting of HER2, thereby increasing ADC payload release and reducing tumor recurrence after T-DXd treatment. These findings explain the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors. This new model and therapeutic strategy may play a crucial role in improving the survival rate of patients with HER2-positive breast cancer and personalizing their treatment. This study highlights the importance of considering intratumor heterogeneity in the development of targeted therapies, and further detailed research will be necessary in the future.
Intratumor heterogeneity for HER2 in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. Here we describe human HER2 heterogeneous breast cancer models composed of ERBB2 amplified (HER2hi) and non-amplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) like T-DXd but are sensitive to HER2 kinase inhibitors. CRISPR screens in heterogeneous co-cultures identified sensitizers of HER2lo cells to T-DXd including ABCC1 and USP9X. USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.
This study deepens our understanding of the internal heterogeneity of HER2-positive breast cancer and its targeted therapies. By modeling internal heterogeneity and providing new strategies to overcome resistance to treatment, this research may contribute to improving the survival rate of patients with these tumors. Furthermore, this study emphasizes the need for personalized treatment development that takes into account internal heterogeneity. The development of effective treatments for HER2 heterogeneous breast cancer is crucial, and this research provides valuable insights into the complex interactions between different cell populations within the tumor.