Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

Abstract

Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20–25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.

Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

“…Immune checkpoint inhibitors, EZH2 antagonists, poly(ADP‐ribose) polymerase inhibitors and various other targeted therapies or specific chemotherapy regimens have been proposed for use in SWI/SNF complex‐deficient cases 45–48 . For example, EZH2 antagonists have been proposed as a rational therapeutic choice in SMARCA4‐deficient brain or ovarian tumours 46,47 .…”

“…[42][43][44] Immune checkpoint inhibitors, EZH2 antagonists, poly (ADP-ribose) polymerase inhibitors and various other targeted therapies or specific chemotherapy regimens have been proposed for use in SWI/SNF complex-deficient cases. [45][46][47][48] For example, EZH2 antagonists have been proposed as a rational therapeutic choice in SMARCA4deficient brain or ovarian tumours. 46,47 This approach should currently be considered to be experimental, and if novel therapies for SWI/SNF complex-deficient tumours are validated it will become a challenge to identify them in clinical practice.…”

Rare Subtype of Endometrial Cancer: Undifferentiated/Dedifferentiated Endometrial Carcinoma, from Genetic Aspects to Clinical Practice

“…ARID1A and ARID1B co-inactivation appears to be an alternate mechanism to BRG1 or INI1, which results in the occurrence of the undifferentiated component [ 23 ]. Overall, ARID1A is the most frequently mutated SWI/SNF subunit across cancer types [ 29 ] and has a tumor-suppressive function, whereby it triggers cancer development by interfering with the DNA-damage response and cell cycle pathways [ 32 , 33 ]. Furthermore, several studies have also demonstrated that an ARID1A loss is associated with the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and the concurrent loss of PTEN expression, which both activate the PI3K/AKT/ mTOR cell cycle pathway [ 34 , 35 , 36 , 37 ].…”

“…Proteolysis-targeting chimeras induce ubiquitin transfer onto target proteins, thereby marking them for proteasomal degradation. This was applied to target BRD9, a SWI/SNF complex subunit [ 33 ]. For example, AU-15330 induced a potent inhibitor of tumor growth in xenograft models of prostate cancer, and synergized with the androgen receptor antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer models without toxicity [ 60 ].…”

“…Wild-type ARID1A downregulated the expression of Aurora A, while ARID1A loss led to increased expression levels of Aurora A and activated the cell division cycle. Thus, the inhibition of Aurora A with a kinase inhibitor induced a G2/M phase arrest, followed by apoptosis [ 33 ]. Alisertib as an Aurora A kinase inhibitor has recently been used in phase 3 randomized trials for hematologic malignancy.…”