Cotargeting the lncRNA-PIP3 Interaction and AKT/PI3K Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer
Technical Report,04 May 2017,14 Sep 2018
University of Texas MD Anderson Cancer Center Houston, United States
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Triple-negative breast cancers TNBC does not respond to endocrine therapies or HER2-targeted therapies are difficult to attack. Hyperactive AKTPI3K signaling is a common feature of TNBC and its inhibition has potent antitumor consequences. Unfortunately, targeted cancer therapy results in short-lived benefits that are followed by acquired resistance that arises through unknown mechanisms. Long noncoding RNAs lncRNAs are aberrantly expressed in a broad spectrum of cancers, including breast cancer, and play key roles in promoting and maintaining cancer cell characteristics, which makes these molecules attractive therapeutic targets. We identified the expression of a lncRNA, LINK-A is upregulated in TNBC tissues compared to non-TNBC breast cancer tissues. LINK-A associated with cellular lipid components which promotes EGF-induced AKT activation. The proposed study will identify the mechanism by which lncRNAs regulate the AKTPI3K pathway in order to devise a co-targeting strategy. To address our hypothesis that LINK-A functions to regulate PI3K-AKT signaling pathway via its interaction with PIP3 in TNBC cells and that this mechanism may impact the efficacy of PI3K-AKT inhibition, we will identify the mechanism by which specific LINKA-PIP3 interactions influence AKT activation examine the functional role of LINK-A in regulating PI3K-AKT pathway in TNBC and evaluate the effects of combined inhibition of LINK-A with pharmacologic inhibitors of PI3K-AKT pathway on TNBC progression. The results from the proposed study will bring innovative and cogent lncRNA-based tactics to attack central problems in breast cancer research and offer a notable advance in the fight against TNBC by highlighting lncRNAs as a class of drug targets for breast cancer metastasis.
- Medicine and Medical Research