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