MYC and HSF1 Cooperate to Drive Sensitivity to Polo-like Kinase 1 Inhibitor Volasertib in High Grade Serous Ovarian Cancer.

Abstract

Ovarian cancer is a deadly gynecological disease with frequent recurrence. Current treatments for patients include platinum-based therapy regimens with PARP inhibitors specific for HR-deficient high-grade serous ovarian cancers (HGSOCs). Despite initial effectiveness, patients inevitably develop disease progression as tumor cells acquire resistance. Toward the development of new therapeutic avenues, we describe a gene amplification involving both HSF1 and MYC, wherein these two genes are co-amplified in over 30% of HGSCO patients. We further found that HSF1 and MYC transcriptional activity was highly correlated in human HGSOC tumors and cell lines, suggesting they may cooperate in the disease. CUT&RUN for HSF1 and MYC revealed overlapping HSF1 and MYC binding throughout the genome. Moreover, binding peaks of both transcription factors in HGSOC cells were nearly identical, and a protein-protein interaction between HSF1 and MYC was detected, supporting molecular cooperation. Supporting a functional cooperation of these two transcription factors, growth of HGSOC cells with the co-amplification was dependent on both HSF1 and MYC. To identify a therapeutic target that could take advantage of this unique HSF1 and MYC dependency, polo-like kinase 1 (PLK1) was correlated with HSF1 and MYC in HGSOC specimens. Targeting PLK1 with volasertib revealed a greater than 200-fold increased potency in HSF1-MYC co-amplified HGSOC cells compared to those with wild-type HSF1 and MYC copy number. Although the success of volasertib and other PLK1 inhibitors in clinical trials has been modest, the current study suggests that targeting PLK1 in a precision medicine approach using HSF1-MYC co-amplification as a biomarker in HGSOC.