National University of Singapore
CHARACTERISATION OF A NOVEL SMALL MOLECULE INHIBITOR FOR IMMUNE ACTIVATION IN TRIPLE NEGATIVE BREAST CANCER
Abstract
dc:description.abstractTriple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment options. Our group has previously identified a novel small molecule inhibitor, CHL-4, whose anti-tumour effects function through Lyn kinase, a member of the Src family kinases. This current study characterised a novel immunomodulatory role for CHL-4, which is able to increase gene and protein expression of Type I/III IFNs in TNBC cell lines. This signalling is dependent on the RIG/MAVS cytosolic RNA-sensing pathway, and is possibly triggered by increased cytosolic localisation of mitochondrial dsRNA. Using a 3D vascularised TNBC model, CHL-4 treatment increased peritumour accumulation of PBMCs compared to control treatment. Furthermore, combination treatment with anti-PD-L1 inhibitor Atezolizumab increased IFN-γ production by PBMCs. Interestingly, the immunomodulatory effects of CHL-4 are not mediated by Lyn kinase, but by another yet-to-be-identified target. Future work will focus on identification of novel targets for CHL-4 and further elucidation of its mechanism of action. Taken together, the identification of an additional mechanism of action of CHL-4 provides further support for its use as a therapeutic option in TNBC.
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- LEE E HUI CLARISSA