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bioRxiv · 10.1101/2024.06.11.598486

MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer

Williams, I.·DeHart, H.·O'Malley, M.·Walker, B.·Ulhaskumar, V.·Ray, H.·Delaney, J. R.·Nephew, K. P.·Carpenter, R. L.
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Abstract

Ovarian cancer is a deadly female cancer with high rates of recurrence. The primary treatment strategy for patients is platinum-based therapy regimens that almost universally develop resistance. Consequently, new therapeutic avenues are needed to overcome the plateau that current therapies have on patient outcomes. We describe a gene amplification involving both HSF1 and MYC, wherein these two genes on chromosome 8q are co-amplified in over 7% of human tumors that is enriched to over 30% of patients with ovarian cancer. We further found that HSF1 and MYC transcriptional activity is correlated in human tumors and ovarian cancer cell lines, suggesting they may cooperate in ovarian cancer cells. CUT&RUN for HSF1 and MYC in co-amplified ovarian cancer cells revealed that HSF1 and MYC have overlapping binding at a substantial number of locations throughout the genome where their binding peaks are near identical. Consistent with these data, a protein-protein interaction between HSF1 and MYC was detected in ovarian cancer cells, implying these two transcription factors have a molecular cooperation. Further supporting their cooperation, growth of HSF1-MYC co-amplified ovarian cancer cells were found to be dependent on both HSF1 and MYC. In an attempt to identify a therapeutic target that could take advantage of this dependency on both HSF1 and MYC, PLK1 was identified as being correlated with HSF1 and MYC in primary human tumor specimens, consistent with a previously established effect of PLK1 on HSF1 and MYC protein levels. Targeting PLK1 with the compound volasertib (BI-6727) revealed a greater than 200-fold increased potency of volasertib in HSF1-MYC co-amplified ovarian cancer cells compared to ovarian cancer cells wild-type HSF1 and MYC copy number, which extended to several growth assays, including spheroid growth. Volasertib, and other PLK1 inhibitors, have not shown great success in clinical trials and this study suggests that targeting PLK1 may be viable in a precision medicine approach using HSF1-MYC co-amplification as a biomarker for response.

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Williams, I., DeHart, H., O'Malley, M., Walker, B., Ulhaskumar, V., Ray, H., Delaney, J. R., Nephew, K. P., Carpenter, R. L.. 2024-06-13. MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer. https://doi.org/10.1101/2024.06.11.598486

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