Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Abstract

Significance Ovarian cancer has the propensity for early dissemination of microscopic metastases, making early detection challenging. Development of treatments for patients with advanced/recurrent chemotherapy-resistant disease remains an unmet need. We sequenced primary, synchronous bilateral ovarian cancer (SBOC), metastatic, and recurrent ovarian tumors. We found primary and metastatic tumors to be remarkably similar and SBOC to be clonally related in all cases, suggesting early dissemination to represent an intrinsic feature of ovarian cancer. c-MYC and PIK3CA amplifications were prevalent and maintained in progression to metastasis and enriched in tumor recurrence. c-MYC amplified chemotherapy-resistant cell lines and xenografts were sensitive to JQ1 and GS-626510, suggesting Bromodomain and Extra-Terminal motif (BET) inhibitors as effective targeted agents in patients with c-MYC–amplified recurrent/chemotherapy-resistant ovarian tumors.