LAUSR

1065 Background: Triple-negative breast cancer (TNBC) has been shown to display cyclin-dependent kinase 7 (CDK7)-dependent transcriptional addition and is sensitive to a CDK7 inhibitor THZ1. As tumor heterogeneity is well known, we sought to identify predictive markers of sensitivity to CDK7 inhibition in TNBC. Methods: Published mRNA microarray data was analyzed to identify genes associated with sensitivity of TNBC cells to the CDK7 inhibitor THZ1. Cell survival assay after THZ1 treatment was performed using Cell Counting Kit-8. Expression of SOX9 was examined by Western blot in cell lines and IHC in breast cancer tissue microarray. Patient survival analysis was done using the Kaplan-Meier method. Results: Analysis of published mRNA microarray data showed that SOX9 was overexpressed in the MDA-468 and BT-549 TNBC cell lines, which were sensitive to the CDK7 inhibitor THZ1 and showed decreased SOX9 expression with THZ1 treatment. We treated 10 TNBC cell lines with various concentrations of THZ1 and found that these cell lines displayed a wide spectrum of sensitivity to THZ1, with an IC50 ranging from 20-30 nM in sensitive lines (MDA-468 and MDA-231) to ~300 nM in insensitive lines (BT-20 and MDA-157). There was a strong correlation of SOX9 expression by Western blot and sensitivity to THZ1 in these cell lines (Pearson correlation, r = 0.82, P= 0.01). IHC of two tissue microarrays containing 278 breast cancer samples showed that SOX9 expression was significantly higher in TNBC (n = 59) compared to hormone positive breast cancer (n = 173; P< 0.01). Among the 59 TNBC cases, 43 had high SOX9 expression and 16 had low SOX9 expression. Patients with high or low SOX expression had similar grade, T stage and nodal involvement (All P> 0.20). Finally, with standard of care treatment, TNBC patients with high SOX9 expression had a significantly worse overall survival (OS) compared to patients with low SOX9 expression (2 year OS rate 100% vs 92.9%, 5 year OS rate 93.8% vs 83.3%, log rank P= 0.03). Conclusions: SOX9 expression level in TNBC cell lines was associated with sensitivity to the CDK7 inhibitor THZ1. TNBC patients with high expression of SOX9 had worse OS, and may benefit from CDK7 inhibition as a novel therapy.