Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Abstract

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 and activating mutations in the PI3K subunit 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. In a large set of patients with OCCC ( = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines ( = 17) and OCCC patient-derived xenografts ( = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. 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. These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. .

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

“…With the development of the mTOR pathway, many scientists have studied the effects of mTOR inhibitors in different tumors [48,[56][57][58]. Because conventional platinum chemotherapy failed to respond to ovarian clear cell carcinoma (OCCC), Caumanns et al [59] conducted drug testing of mtorc1/2 inhibitor AZ D8055 in the OCCC cell lines. The results showed that the OCCC cell line was sensitive to AZD8055, and AZD8055 was validated in a xenotransplantation model.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…However, a phase II trial that studied AZD2014 versus everolimus found AZD2014 to be inferior in treating patients with VEGF-refractory renal cell carcinoma and led to early termination of the study [201]. Kinome profiling of samples from patients with advanced-stage ovarian clear cell carcinoma (OCCC) revealed increased alterations in the PI3K/Akt/mTOR pathway in about 91% of tumors [285]. The majority of the OCCC cell lines tested displayed more sensitivity to mTORC1/2 inhibition (AZD8055) than to drugs targeting the ERBB family of RTKs or to inhibitors of DNA repair signaling.…”

Downregulation of the ubiquitin ligase KBTBD8 prevented epithelial ovarian cancer progression

“…Furthermore, we discovered that KBTBD8 knockdown inactivated multiple essential kinases. Gene mutation or amplification of mTOR, Erk, Akt, or β-catenin has been frequently characterized in human high-grade ovarian cancer and is positively correlated with drug resistance (Caumanns et al 2018 ; Rahman et al 2013 ; Davies et al 2015 ; Wu et al 2001 ; Palacios et al 1998 ), while the downregulation of any of these genes appears to inhibit ovarian cancer progression and promote drug sensitization (Pétigny-Lechartier et al 2017 ; Lu et al 2014 ; Au-Yeung et al 2017 ; Chartier et al 2016 ). As these kinases have also been shown to be important for female fertility, KBTBD8 is thus important not only for the normal function of ovarian epithelial cells, but also for the normal fertility.…”