Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies

Ying Wei; Sonia Erfani; David Schweer; Rafael de Gouvea; Javeria Qadir; Junfeng Shi; Kai Cheng; Dabao Wu; Rolf Craven; Yadi Wu; Thibault Olivier; Lauren A Baldwin; Binhua Zhou; Ying Zhou; Weidong Zhao; Burton B Yang; Frederick R Ueland; Xiuwei H Yang

doi:10.1016/j.omto.2023.02.006

Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies

Mol Ther Oncolytics. 2023 Feb 19:28:293-306. doi: 10.1016/j.omto.2023.02.006. eCollection 2023 Mar 16.

Authors

Ying Wei¹, Sonia Erfani^{2

3}, David Schweer⁴, Rafael de Gouvea^{2

5}, Javeria Qadir⁶, Junfeng Shi^{2

4

7}, Kai Cheng⁸, Dabao Wu¹, Rolf Craven², Yadi Wu^{2

4}, Thibault Olivier², Lauren A Baldwin⁴, Binhua Zhou⁴, Ying Zhou¹, Weidong Zhao¹, Burton B Yang⁶, Frederick R Ueland⁴, Xiuwei H Yang²

Affiliations

¹ Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science & Technology of China, Hefei, Anhui Province, P.R. China.
² Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA.
³ Pharmacy Services, University of Kentucky Medical Center, Lexington, KY, USA.
⁴ Markey Cancer Center and College of Medicine, University of Kentucky, Lexington, KY, USA.
⁵ College of Literature Science and Arts, University of Michigan, Ann Arbor, MI, USA.
⁶ Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁷ Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.
⁸ Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, P.R. China.

Abstract

Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide. Receptor tyrosine kinases (RTKs) have long been sought as therapeutic targets for EOC, as they are frequently hyperactivated in primary tumors and drive disease relapse, progression, and metastasis. More recently, these oncogenic drivers have been implicated in EOC response to poly(ADP-ribose) polymerase (PARP) inhibitors and epigenome-interfering agents. This evidence revives RTKs as promising targets for therapeutic intervention of EOC. This review summarizes recent studies on the role of RTKs in EOC malignancy and the use of their inhibitors for clinical treatment. Our focus is on the ERBB family, c-Met, and VEGFR, as they are linked to drug resistance and targetable using commercially available drugs. The importance of these RTKs and their inhibitors is highlighted by their impact on signal transduction and intratumoral heterogeneity in EOC and successful use as maintenance therapy in the clinic through suppression of the VEGF/VEGFR axis. Finally, the therapeutic potential of RTK inhibitors is discussed in the context of combinatorial targeting via co-inhibiting proliferative and anti-apoptotic pathways, epigenomic/transcriptional programs, and harnessing the efficacy of PARP inhibitors and programmed cell death 1/ligand 1 immune checkpoint therapies.

Keywords: EGFR; ERBB2; MET; VEGFR; ovarian cancer; receptor tyrosine kinases; targeted therapy.

Publication types

Review

Grants and funding

R01 CA230758/CA/NCI NIH HHS/United States