A New Persistence Mechanism for Drug-Tolerant Breast Cancer Cells
Abstract
The Overarching Challenge is “to identify what drives breast cancer growth and determine how to stop it.” Over the last decade, the use of targeted therapies with specific inhibitors of tumor growth-promoting proteins that localize to the cell surface has greatly improved the outcome for a number of malignancies, including breast cancer (BrCA). Such tumor-driving signaling proteins include members (1-4) of the EGFR/HER Protein Tyrosine Kinase family and also Insulin Growth Factor 1 Receptor (IGF1R). Unfortunately, eventual acquired resistance to such tyrosine kinase inhibitors (TKIs) is inevitable, and the development of novel effective therapies for these patients is critical. Acquired resistance mechanisms that develop under months of therapy pressure (such as single anti-HER or pan-HER TKIs) are mediated by DNA modifications and mirror the common clinical scenario where the BrCA response is followed by relapse due to an acquired genetically based resistance mechanism. Emerging evidence suggests that non-genetic mechanisms are involved in the protection of an early subset of tumor cells, drug-tolerant persister cells, that maintain viability under antitumor treatments by non-mutational mechanisms until genetic-based mechanisms are developed. This unique survival capability is considered to be the core for the emergence of drug-resistant tumors. This phenomenon has been observed across a wide range of cancer lineages with both chemotherapy and targeted therapy. Targeting non-mutational resistance may therefore present a therapeutic opportunity to eliminate residual surviving tumor cells to prevent relapse. Our preliminary results have identified such a non-mutational resistance mechanism that fits the proposed model of BrCA persister cells. Furthermore, we have also identified molecular components of the resistance mechanism that provide a route to clinical translation of the findings. In our preliminary studies, we obtained evidence that caspase-9 (CASP9), a protein known for its involvement in a cell death mechanism, is also involved in a non-apoptotic mechanism that enhances the cell surface expression of signaling receptors (HER1 and IGF1R) that are significant for BrCA tumorigenesis. We also obtained evidence that CASP9 is involved in mediating the initial (non-mutational) tolerance to anti-HER treatments, allowing the surviving (persisting) BrCA cells to acquire (over time) genetic mechanisms of therapy resistance that facilitate the disease progression. The specific aims for this study are designed to (i) investigate the tumor protective function of CASP9 in early tolerant and late persister BrCA cells that are CASP9-dependent in their resistance to pan-HER TKI therapies; (ii) to elucidate the molecular determinants underlying the cell protective function of CASP9 and to ascertain a neutralization approach for this non-genetic resistance mechanism; and (iii) to determine the impact of CASP9 on BrCA growth and response to therapy in animal models. Successful completion of these studies may lead to the development of a novel therapeutic strategy to alleviate resistance to pan-HER TKIs in the clinic. Patients that have progressed on anti-HER2 antibody treatment and/or progressed on (subsequent) pan-HER inhibitors will ultimately benefit from a successful outcome of this study. Upon their outgrowth, BrCA persister cells can develop multiple genetically based resistance mechanisms that are commonly observed in the clinic. Therefore, understanding the non-apoptotic function of CASP9 and targeting it to prevent pan-HER TKI resistance and persistence would be applicable to the majority of cases of acquired resistance seen in the clinic. The proposed studies are focused on the molecular mechanisms involved in CASP9 protection of pan-HER TKI-targeted BrCA persister cells and on elucidation of a potential pathway to a translatable treatment. The proposed studies are also highly innovative, as the p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010005
Entities
People
- Hannah Rabinowich
Organizations
- United States Army
- University of Pittsburgh