Abstract 2486: Dissecting the lineage specific roles of BCL-XL in breast cancer metastasis

Abstract

Abstract B-cell lymphoma X-large (BCL-XL) is a member of the BCL-2 protein family and has been known as an anti-apoptotic protein. As a viable target for cancer therapy, we recently found that proteolysis-targeting chimeras (PROTAC, currently under phase I clinical investigation) against BCL-XL kill cancer cells as well as tumor-induced regulatory T cells (TI-Tregs). Interestingly, BCL-XL has been shown to promote breast cancer metastasis via a function independent of its anti-apoptotic function. We reason that 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. To our surprise, our pilot experiments using two syngeneic breast cancer models showed opposite 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, suggesting the on-targeting but contrasting function of BCL-XL in breast cancer metastasis. Our central hypothesis is that BCL-XL may play different roles in breast cancer metastasis depending on the genetics/proteomics of cellular cues from different cancer cells. To confirm the function of BCL-XL in different breast cancer cell lines, we generated BCL-XL KO lines from 4 other syngeneic mouse breast cancers. We confirmed that the majority of breast cancer cells depend on BCL-XL for metastasis, including 4T1, AT-3, E0771.lmb etc; whereas only the Py8119 model exhibits an opposite phenotype. For primary tumor growth, AT-3 and E0771.lmb cells grow bigger tumors in the WT group than in the BCL-XL KO group; and 4T1 and Py8119 cells exhibit similar tumor growth rate between WT and KO cells. For metastatic breast cancer therapy, we treated 4T1-tumor bearing mice with BCL-XL-targeting PROTAC that nearly significantly reduces metastatic spread in the lung without significant change in primary tumor growth. In addition, we 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 caution is required as BCL-XL inhibition may be detrimental for certain cancers. Our future effort will focus on the mechanisms explaining why BCL-XL inhibits metastasis in some cancer types, which can be used as an exclusion criterion for BCL-XL-targeting therapy. Citation Format: Madison E. Carelock, Mo Jiao, Weizhou Zhang. Dissecting the lineage specific roles of BCL-XL in breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2486.