Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies-Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

Keywords: ARID1A; ARID1B; BAF chromatin-remodelling complex; SMARCA2; SMARCA4; SWI/SNF chromatin-remodelling complex; Small cell carcinoma of the ovary; endometrioid ovarian cancer (EnOC); endometriosis; hypercalcaemic type (SCCOHT); ovarian clear cell carcinoma (OCCC).

Figure 1

The distribution of loss-of-function alterations in mammalian SWI/SNF (mSWI/SNF) chromatin-remodelling complex members across ovarian cancer histopathological subtypes. The schematic uses the canonical BAF (cBAF) formation of the SWI/SNF complex to depict subunit involvement. A loss-of-function alteration is defined as the presence of a pathogenic mutation in the encoding gene and/or the loss of corresponding protein expression. “Higher association with the SWI/SNF complex” is defined as subtypes where over 20% of cases have alterations in at least one complex member. An exception was made for undifferentiated/dedifferentiated ovarian cancers due to limited incidence reporting. Complex members identified as altered in over 40% of a specific subtype are indicated in bold and underline. An alteration is presented as ‘rare’ if less than 10 cases were reported in the published literature or large cohort analyses (N ≥ 100) report an incidence less than 10%. Distribution is based on data in Tables 2 and 3 and Tessier-Cloutier and colleagues [30]. Created with www.BioRender.com, Access Date: 9 August 2024.

Figure 2

Therapeutic drugs investigated in patients with OCCC or SCCOHT and pre-clinical models of these tumours. Molecular targeted therapies including immune checkpoint inhibitors, epigenetic inhibitors, PARP inhibitors and kinase inhibitors have been trialled in patients with OCCC or SCCOHT, as well as in vitro and in vivo pre-clinical models ^ of these malignancies. Where patients did not respond to, or tolerate, a drug, this is indicated by ^#. Drugs listed were administered to patients or tested in pre-clinical models either as monotherapies or in conjunction with other drug(s). A higher TMB is reported for OCCC, indicated by a green arrow, while SCCOHT has a low TMB, indicated by a red arrow. Both OCCC and SCCOHT have TILs. Both tumour types have high levels of PD-L1. Therapeutic drugs tested in OCCC patients, include pembrolizumab [154], durvalumab [155], toripalimab [156], olaparib [157], everolimus [156], and dasatinib [158], and in pre-clinical models include iBET-762 [159], ACY1215 [160], CPI203 [159], ceralasertib [161] and tulmimetostat [162]. Therapeutic drugs tested in SCCOHT patients include nivolumab [163], ipilimumab [163], pembrolizumab [103,164], durvalumab [108], olaparib [108,163], tazemetostat [165], abemaciclib [163], palbociclib [108] and ponatinib [163], and in pre-clinical models include GSK126 [166], OTX015 [167], tazemetostat [166,168] and palbociclib [169]. Drugs trialled in patients were on occasion administered either sequentially, informed by patient response, or together. Drug combinations of this nature in OCCC patients included pembrolizumab (combined with bevacizumab and cyclophosphamide) [154], pembrolizumab (combined with bevacizumab and olaparib) [157], and toripalimab (combined with everolimus) [156]. Drug combinations trialled in SCCOHT patients included pembrolizumab (following cycles of cisplatin/etoposide and carboplatin/paclitaxel) [103], nivolumab and ipilimumab (followed by ponatinib, abemaciclib and olaparib) [163]. In a single case report, a SCCOHT patient was administered six lines of chemotherapy of multiple drugs that included durvalumab, olaparib and palbociclib [108]. Abbreviations: ATR, Ataxia-telangiectasia-mutated (ATM) and RAD3-related; BET, bromo- and extra-terminal domain family; CDK4/6, cyclin-dependent kinases 4 and 6; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EZH1/2, Enhancer Of Zeste 1/2 Polycomb repressive complex 2 subunit; HDAC6, histone deacetylase 6; mTOR, mammalian target of rapamycin; OCCC, ovarian clear cell carcinoma; PARP, Poly (ADP-ribose) polymerase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SCCOHT, Small cell carcinoma of the ovary, hypercalcaemic type; TILS, Tumour-infiltrating lymphocytes; TMB, tumour mutational burden. Both tumour types also have high levels of PD-L1. Created with www.BioRender.com, Access Date: 9 August 2024.