Abstract P1-09-08: BCL2L1 (BCL-XL) expression and MYC super-enhancer positivity predict sensitivity to the covalent CDK7 inhibitor SY-1365 in triple negative breast cancer (TNBC) cell lines
Authors: Rajagopal N , Hodgson G , Hu S , McKeown M , Bush A , Fritz C , Orlando D , Olson E , di Tomaso E 
Published: February 2018

Effective therapies for TNBC remain elusive. As such, TNBCs are associated with a high risk of relapse and short progression free- and overall-survival. Recent studies showed that TNBC cells are highly dependent on the transcriptional regulator CDK7, and suggest that the mitochondrial apoptosis pathway is important in mediating cell survival in CDK7-dependent cells. Further, TNBC has been shown to have a distinct epigenetic and transcriptional program, with super-enhancers (SE) mediating the expression of key oncogenic drivers such as MYC. SY-1365, a covalent and selective inhibitor of CDK7, was developed to exploit dysregulated programs thought to drive SE-mediated transcriptional-dependencies in TNBC and other cancers. To identify potential biomarkers predictive of sensitivity to SY-1365, we evaluated SY-1365 inhibitory activity in a large panel of human tumor cell lines, including TNBC lines, and correlated sensitivity with RNA expression and epigenetic profiles.

SY-1365 dose-response curves were measured using the ATP-lite assay in a panel of 406 human tumor cell lines, including 19 TNBC cell lines. Clustering of growth-rate adjusted dose response curves of cell-lines treated with SY-1365 allowed the classification of cell-lines into low and high response groups. An unbiased genome wide approach was used to compare response classification to RNA expression data across all cell lines to identify gene expression markers predictive of sensitivity to SY-1365. Furthermore, a hypothesis driven approach was followed to interrogate whether the MYC SE predicted sensitivity to SY-1365.

Twenty-five genes were differentially expressed between SY-1365-sensitive and -insensitive tumor lines (FDR&lt;0.05). Lower expression of BCL2L1, which encodes the mitochondrial apoptosis regulator BCL-XL, was identified as the most predictive expression biomarker of sensitivity across all profiled cell lines, strongly separating the two classes of sensitivity (Accuracy=70%, FDR&lt;0.005). Further, this predictive power of lower BCL2L1 expression was maintained in an analysis restricted to the subset of TNBC cell-lines (Accuracy=73%).

Expanding beyond expression analysis, we also found that the strength of the MYC SE (as defined by H3K27Ac) was predictive of response to SY-1365 in TNBC (Accuracy=86%, FDR&lt;0.05).

In this study, we show for the first time that SY-1365 induced differential responses across a large panel of human tumor cell lines derived from multiple indications. We also show that in this panel of cell lines the response could be predicted in an “indication agnostic” manner by the level of expression of BCL2L1. Finally, in line with prior reports, in TNBC cell lines, MYC SE was significantly associated with sensitivity to SY-1365. These observations have generated strong hypotheses for selection strategies aimed at identifying patients with tumors particularly sensitive to CDK7 inhibition with SY-1365, and warrant further investigation with respect to predictive biomarkers of response in patients. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors, including a planned expansion cohort enriching for patients with TNBC (NCT03134638).

Citation Format: Rajagopal N, Hodgson G, Hu S, McKeown M, Bush A, Fritz C, Orlando D, Olson E, di Tomaso E. BCL2L1 (BCL-XL) expression and MYC super-enhancer positivity predict sensitivity to the covalent CDK7 inhibitor SY-1365 in triple negative breast cancer (TNBC) cell lines [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-08.