Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

Abstract

Epigenetic remodeling and metabolic reprogramming, two well-known cancer hallmarks, are highly intertwined. In addition to their abilities to confer cancer cell growth advantage, these alterations play a critical role in dynamically shaping the tumor microenvironment and antitumor immunity. Recent studies point toward the interplay between epigenetic regulation and metabolic rewiring as a potentially targetable Achilles' heel in cancer. In this review, we explore the key metabolic mechanisms that underpin the immunomodulatory role of AT-rich interaction domain 1A (ARID1A), the most frequently mutated epigenetic regulator across human cancers. We will summarize the recent advances in targeting ARID1A-deficient cancers by harnessing immune-metabolic vulnerability elicited by ARID1A deficiency to stimulate antitumor immune response, and ultimately, to improve patient outcome.

Keywords: ARID1A; cancer immunotherapy; chromatin remodeling; metabolism.

Figure 1

Bibliometric analysis of publications using “ARID1A”, “Cancer” and “Metabolism” as search terms. We searched the PubMed to perform bibliometric analysis, using “ARID1A”, “Cancer” and “Metabolism” as search terms. The number of published articles has increased each year, in particular, during the past 10 years.

Figure 2

Cancer type-specific ARID1A dependency. Shown is the ARID1A dependency score across 32 cancer types comparing cancers with ARID1A mutations (red dots) versus wildtype (black dots). Dependency scores were calculated for each cell line using data from DepMap database version 22Q2 as an average gene score from RNAi (Achilles + DRIVE + Marcotte, DEMETER2) [35,36] and CRISPR (DepMap 22Q2 Public + Score, Chronos) [37] screens. Negative scores represent more dependent cells, which have reduced proliferation after gene depletion by CRISPR/Cas9 or RNAi. Detailed description is provided in [38]. Data for ARID1A mutations in cancer cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE) database and only damaging mutations are shown. Note that cancer cells with ARID1A mutations are less affected by ARID1A depletion than those without ARID1A mutations (wildtype ARID1A), as shown by most red dots placed higher than the median values for that cell type.

Figure 3

Distribution of cancer type-specific ARID1B dependency. Shown is the ARID1B dependency across 32 cancer types comparing cancers with ARID1A mutations (red dots) versus wildtype (black dots). Dependency scores were calculated for each cell line as in Figure 2. Note that most cancer cells with the highest ARID1B dependency (lower than 0.5) have ARID1A mutations.