Abstract 420: Translational strategy for targeting MCL1 amplified tumors with CDK9 inhibitor

BCL-2, BCL-XL, and MCL-1 are members of the prosurvival family of proteins that regulate the mitochondrial apoptotic pathway. These proteins are often amplified or overexpressed in multiple tumor types. Previously, we showed that non-small cell lung cancer (NSCLC) cell lines with low BCL-XL expression (high MCL-1 / BCL-XL ratio) are MCL-1-dependent. TCGA data shows MCL1 amplification is one of the frequent genetic events in NSCLC adenocarcinoma (20%) and breast cancer (15%), while BCL2 is frequently amplified in activated B-cell like diffuse large B cell lymphoma (11%) and BCL2L1 in colorectal cancer (15%). We hypothesize that cancer cell lines with MCL1 amplification and/or high MCL-1 / BCL-XL ratio depend on MCL-1 for survival and are sensitive to inhibition of CDK9, a component of the transcriptional elongation complex that regulates MCL-1 expression. In this study, we demonstrate that NSCLC, triple negative breast cancer (TNBC) and ovarian cell lines with amplified MCL1 or low BCL-XL expression (high MCL-1 / BCL-XL expression ratio) are MCL-1-dependent, and are sensitive to dinaciclib, a CDK9 inhibitor. Cell lines with high BCL-XL expression could be re-sensitized to dinaciclib when co-treated with BCL2/BCL-XL inhibitor navitoclax (ABT-263) or BCL-XL-selective inhibitor A-1155463, suggesting BCL-XL as a resistance factor. Indeed, exogenous expression of BCL-XL rescues sensitive cell lines from dinaciclib. As reported in TCGA, ovarian, NSCLC and TNBC patients with MCL1 amplification also have high MCL-1 expression, and we hypothesized that these patients to be sensitive to CDK9 inhibitors. We developed a fluorescence in situ hybridization (FISH) assay to detect MCL1 amplification which can potentially select patients that may benefit from dinaciclib treatment. We show that fifteen percent of NSCLC patients have high MCL1 amplification, similar to published data. In addition, we have identified other predictive biomarkers associated with sensitivity in TNBC cell lines from gene expression analysis. In conclusion, we have developed a translational strategy for identifying MCL-1-dependent cancers that may be sensitive to CDK9 inhibitors in the clinic. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication Citation Format: Ziping Yang, Ricky Bellin, Paul Hessler, Xin Lu, Tamar Uziel, Lloyd T. Lam. Translational strategy for targeting MCL1 amplified tumors with CDK9 inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 420.