EZH2 inhibition in ARID1A mutated clear cell and endometrioid ovarian and endometrioid endometrial cancers

Abstract

Clear cell carcinoma and endometrioid adenocarcinoma are histologic subtypes of ovarian and uterine cancer that demonstrate unique clinical behavior but share common underlying genomic aberrations and oncogenic pathways. ARID1A mutations are more frequently identified in these tumors, in comparison to other gynecologic histologies, and loss of ARID1A tumor suppressor function is thought to be an essential component of carcinogenic transformation. Several therapeutic targets in ARID1A mutated cancers are in development, including EZH2 inhibitors. EZH2 facilitates epigenetic methylation to modulate gene expression, and both uterine and ovarian cancers show evidence of EZH2 over expression. EZH2 inhibition in ARID1A mutated tumors acts in a synthetically lethal manner to suppress cell growth and promote apoptosis, revealing a unique new therapeutic opportunity. Several phase 1 and 2 clinical trials of EZH2 inhibitors are ongoing currently and there is considerable promise in translational trials for utilization of this new targeted therapy, both to capitalize on ARID1A loss of function and to increase sensitivity to platinum-based adjuvant chemotherapies. This review will synthesize the molecular carcinogenesis of these malignancies and their unique clinical behavior, as a foundation for an emerging frontier of targeted therapeutics – the synergistic inhibition of EZH2 in ARID1A mutated cancers.

Overexpression of enhance of Zeste homolog 2 (EZH2) in endometrial carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

“…However, it is known that the histone methyl transferase activity of EZH2 leads to epigenetic modification of tumor suppressor gene expression and given it is highly expressed in multiple tumor types-EZH2 is an attractive target for drug development in endometrial cancer [24,25]. This line of inquiry is further supported by the primary results of the current study, which confirm that there is differential expression of EZH2 in uterine cancers compared to normal tissues and EZH2 upregulation in many tumors.…”

Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

“…Last, the identification of ARID1A (9.3%) and SMARCA4 (4.1%) mutations may predict sensitivity to an alternate therapeutic strategy. 29 Homeostasis requires balanced ARID1A and EZH2 activity, facilitated via chromatin-mediated gene expression. Loss of ARID1A expression results in imbalanced EZH2 activity, and use of an EZH2 inhibitor such as tazemetostat may capitalize on this oncogene addiction.…”

Sarcomatoid Dedifferentiation in Renal Cell Carcinoma: From Novel Molecular Insights to New Clinical Opportunities

“…Approaches based on multimodal therapy, such as combining stereotactic radiation therapy to bolster immunity, could be interesting to explore in these inflamed tumors [58]. Opportunities for targeted therapies should also be evaluated: cell cycle inhibitors could be interesting in tumors with alterations of cell cycle proteins [59]; approaches targeting chromatin remodeling complexes in tumors already deficient in one or multiple chromatin-remodeling genes, such as ARID1A, could promote synthetic lethality, as demonstrated in other solid tumors [60]; NF2-deficient tumors could be targeted in preclinical models by YAP/TAZ depletion associated with MEK inhibition [31]. The progress made in the metastatic setting may also translate into localized disease.…”