MAPK4 Defines a Subset of Triple-Negative Breast Cancer Vulnerable to Novel Targeted Therapy
Abstract
Triple-negative breast cancers (TNBC) represent about 15%-20% of all breast cancers (BCa). The molecular mechanisms driving TNBC are not well understood, and there is no approved targeted therapy. Therefore, it is essential to investigate the underlying mechanisms driving TNBC and develop novel targeted therapy for this disease. The dysregulation of PI3K activated Akt/mTOR signaling pathway plays important roles in promoting cancer progression. Furthermore, aberrant activation of the PI3K pathway is one of the most common events in TNBC, indicating targeting PI3K might be effective. However, only limited therapeutic response was observed when using PI3K inhibitors to treat TNBC. Regardless of this disappointment, currently there are many ongoing clinical trials to evaluate the therapeutic opportunity using PI3K inhibitors combined with other therapeutics in BCa. MAPK4 is an atypical MAPK with unknown functions in cancer. We discovered that MAPK4 can activate Akt/mTOR signaling pathway in a PI3K-independent manner and that inhibiting MAPK4 in MAPK4-high cancer cells greatly represses their growth. This MAPK4-addiction phenotype identifies targeting MAPK4 as an exciting novel therapeutic avenue. Interestingly, MAPK4 is specifically and highly expressed in 30% or more of TNBC. Therefore, we propose to first investigate whether inhibiting MAPK4 will similarly repress TNBC tumor growth. We will test this using both TNBC cell line-based xenograft models and the patient-derived xenograft (PDX) models. To address why TNBC tumors poorly respond to PI3K inhibitors and to predict/identify/exclude the poor responders from the costly PI3K inhibitor clinical trials, we will also examine whether overexpression/activation of MAPK4 renders TNBC tumors resistant to PI3K inhibitors, whether MAPK4 is induced in TNBC cell lines resistant to PI3K inhibitors, and whether inhibiting MAPK4 sensitizes the resistant TNBC again to PI3K inhibitors. Finally, since the molecular mechanisms driving TNBC are not well understood, we will investigate whether overexpression of MAPK4 (30% or more of TNBC) and loss of p53 with normal function (vast majority of TNBC) provide a direct mechanism for tumorigenesis of TNBC. Our study will address the Overarching Challenge of "Identify what drives breast cancer growth; determine how to stop it." Our proposed study will directly help 30% or more of TNBC patients by exploring MAPK4 as a novel and effective therapeutic target. Since, to the best of our knowledge, we are the only group investigating MAPK4 biology in human cancers, including TNBC, this research field is seriously underdeveloped and no MAPK4-specific inhibitor is available. Therefore, the long-term impact is that our study may potentially revolutionize the care of patients with MAPK4-high TNBCs. The short-term impact includes that by clearly demonstrating the importance of MAPK4 in 30% or more TNBC, our study may draw great attentions from the BCa research community and pharmaceutical companies to develop MAPK4-specific inhibitors for therapy (we are also beginning to screen the DNA-encoded chemical libraries for MAPK4-specific inhibitors; we are trying to secure additional funding and will try our best to move as rapidly as possible on this). Our proposed study may also indirectly help the rest of TNBC patients and this impact may be immediate. By demonstrating the PI3K-independent activity of MAPK4 in driving TNBC and/or MAPK4 driving TNBC resistance to PI3K inhibitors, we will provide the rationale to exclude 30% or more of patients with MAPK4-high TNBC tumors from newly designed/initiated or even the large number of ongoing clinical trials using PI3K inhibitors in TNBC. The exclusion of these large numbers of the predicted none or poor responders may totally change the outcome of these costly clinical trials and may lead to the success of PI3K-targeted therapy for TNBC patients. Finally, inhibiting MAPK4 may also sensitize M
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710043
Entities
People
- Feng Yang
Organizations
- Baylor College of Medicine
- United States Army