Cotargeting the lncRNA-Dependent AKT/PI3K and YAP Signaling: A Novel Paradigm for Treating Triple-Negative Breast Cancer
Abstract
As a deadly disease lacking a Food and Drug Administration-approved targeted therapy, triple-negative breast cancer (TNBC) involves a complicated network of oncogenic processes and has unfavorable outcomes. An emerging class of regulatory RNA molecules known as long noncoding RNAs (lncRNAs) serve as integral mediators of oncogenic signaling pathways, situating them as research subjects of particular interest and potential therapeutic targets. Our preliminary research work revealed that one lncRNA, LINK-A, is specifically upregulated in TNBC and that its expression is correlated with negative breast cancer patient outcomes. LINK-A is concurrently involved in several signaling pathway networks associated with breast cancer initiation, progression, and metastasis, and mammary gland-specific expression of LINK-A results in the development of malignancies that resemble human TNBC both morphologically and transcriptionally. Expression of LINK-A also correlates with diminished immune response as a consequence of its role in disrupting tumor cell recognition machinery. Hence, dissection of the lncRNA-directed molecular mechanisms of TNBC initiation, metastasis, and resistance to immunotherapy is integral to further our understanding of the relationship between lncRNAs and breast cancer and determine an optimized targeted therapy against TNBC. The long-term goal of the proposal is to determine the functional importance of lncRNAs in mediating various oncogenic signaling pathways in order to improve or enhance TNBC treatment strategies and patient outcomes. In this regard, we seek to reduce TNBC mortality by establishing a more comprehensive understanding of the roles of lncRNAs in cancer-related processes. Our central hypothesis is that lncRNAs act as oncogenes that promote breast cancer initiation, metastasis, and immunosuppression through an interconnected network of individual cellular signaling pathways, situating them as potential targets for combinatorial therapies. We will first determine the prognostic value of lncRNAs and the lncRNAs-dependent PKA/YAP pathway in TNBC. We will then dissect the underlying molecular mechanisms of lncRNAs-dependent hyper-activation of the YAP pathway through the crosstalk between lncRNAs, AKT, and PKA. Using three-dimensional culture screening, we will optimize the combinatorial therapy co-targeting lncRNAs, the PI3K/AKT pathway, and the PKA/YAP pathway, and the effectiveness of the combinatorial treatment in repressing mammary gland tumor growth and progression will be determined using the tumor-bearing MMTV-Tg(LINK-A) mice and LINK-A-expressing TNBC PDX models. With respect to outcomes, we expect to identify lncRNA and signaling pathway determinants of breast cancer initiation, risk, susceptibility, and immunosuppression; identify how these interactions contribute to breast cancer growth and determine how to stop them; demonstrate the molecular basis for why some breast cancers become metastatic; and eliminate the mortality associated with metastatic breast cancer through development of a lncRNA and pathway inhibitor-based combinational therapy. The elucidation of these molecular mechanisms will facilitate the development of innovative therapeutic strategies that have the potential to significantly advance TNBC treatment and sensitize TNBC patients to treatment using immune checkpoint blockers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910665
Entities
People
- Liuqing Yang
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army