Dissecting the lineage specific roles of BCL-XL in breast cancer metastasis

Abstract B-cell lymphoma X-large (BCL-XL) has been shown to promote breast cancer metastasis independently of its anti-apoptotic function. We recently found that proteolysis-targeting chimeras (PROTACs) against BCL-XL kill cells as well tumor-induced regulatory T (TI-Tregs). BCL-XL-targeting PROTACs can be potentially used treat metastatic – by direct killing circulating tumor at their vulnerable stages and/or eliciting anti-cancer immunity via T-reg cell depletion. Our pilot experiments showed opposing results with one model showing reduced PROTAC treatment and the other increased metastasis. Genetic deletion (KO) in those two lines reproduces effect on hypothesize may play different roles depending cellular cues from cells. generated 4 syngeneic mouse BCL-XL-KO confirmed most depend for metastasis, whereas only 1 exhibits an opposite phenotype. Additionally, we treated 4T1-tumor bearing mice nearly significantly reduces spread lung. also a systematic inhibition TI-Tregs indicating lineage-specific function conclude is viable therapeutic target treating but further investigation into targeting needed. future efforts will focus investigating why inhibits some types, which exclusion criterion therapy. Supported grants NIH/National Cancer Institute (R01 CA260239)