Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient-derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928-40. ©2018 AACR.
Highlights
In the United States, ovarian cancer is the fifth-leading cause of cancer deaths in women [1]
The majority of patients with ovarian clear cell carcinoma (OCCC) are diagnosed at an early stage (57%–81% at stage I/II) and have better overall survival compared with stage-matched high-grade serous (HGS) ovarian cancer, the most common subtype of ovarian cancer
The majority of genes with a high mutation frequency are implicated in well-known cancer-related pathways like the PI3K/ AKT/mTOR pathway (PIK3CA, PTEN, PIK3R1, and AKT1), MAPK signaling transduction pathway (KRAS), DNA repair pathway (TP53, ATM, and PRKDC), ERBB family of receptor tyrosine kinase genes (ERBB3 and EGFR), and chromatin remodeling genes (ARID1A)
Summary
In the United States, ovarian cancer is the fifth-leading cause of cancer deaths in women [1]. Ovarian clear cell carcinoma (OCCC) is the second most common subtype of epithelial ovarian cancer. The majority of patients with OCCC are diagnosed at an early stage (57%–81% at stage I/II) and have better overall survival compared with stage-matched high-grade serous (HGS) ovarian cancer, the most common subtype of ovarian cancer. In. University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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