Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary

Abstract

Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

Keywords: clear cell carcinoma; genetic mutations; homologous recombination; ovarian cancer; synthetic lethality.

Figure 1.

Landscape of synthetic lethal pairs. Synthetic lethal pairs were divided into four categories: (1) Components of a backup or a parallel pathway with overlapping functions; (2) components encoded by paralogous pairs; (3) Subunit components that form heteromeric complexes; and (4) components that are arranged in a single linear pathway. KRAS, KRAS proto-oncogene, GTPase; Chk, checkpoint kinase; ATR, ATR serine/threonine kinase; ATM, ATM serine/threonine kinase; p53, tumor protein p53; PARP, poly(ADP-ribose) polymerases; PTEN, phosphatase and tensin homolog; ARID1A, AT-rich interaction domain 1A; BRM, SWItch/Sucrose non-fermentable-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2; BRG, SWItch/Sucrose non-fermentable-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4.