Abstract 2759: Colorectal cancer cell lines with high BCL-XL and low MCL-1 expression are sensitive to a potent and selective BCL-XL inhibitor

Abstract

Abstract Colorectal cancer is the second most deadly type of cancer in the United States and worldwide despite the recent approval of new therapies. The identification of novel agents that are effective against this cancer thus remains a significant goal. One hallmark of cancer is the defective regulation of programmed cell death, or apoptosis. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family members, including BCL-2, BCL-XL, and MCL-1, are known to regulate cell survival and death and have been characterized as key survival factors in multiple cancer types. As BCL-XL is overexpressed in many solid tumors, the sensitivity of a panel of 25 colorectal cancer cell lines to a potent and selective BCL-XL inhibitor was investigated. Colorectal cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity, were more sensitive to small molecule BCL-XL inhibition. In contrast, cell lines with lower expression of BCL-XL and higher expression of MCL-1 were resistant. Silencing the expression of BCL-XL via siRNA killed the cell lines that were sensitive to small molecule BCL-XL inhibition while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 restored sensitivity of resistant cells to the BCL-XL inhibitor whereas silencing of NOXA abrogated the sensitivity of cells to BCL-XL inhibitor. BCL-XL inhibition could thus be an effective treatment in a subset of colorectal cancer patients showing high BCL-XL expression. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for the research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Lloyd T. Lam, Haichao Zhang, John Xue, Paul Hessler, Stephen K. Tahir, Jun Chen, Sha Jin, Andrew J. Souers, Joel D. Leverson. Colorectal cancer cell lines with high BCL-XL and low MCL-1 expression are sensitive to a potent and selective BCL-XL inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2759. doi:10.1158/1538-7445.AM2014-2759