Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Abstract

Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/ SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancerselective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

“…The frequency and prevalence of mutations that inactivate chromatin modifi ers in a wide range of human cancers indicate that such mutations are driver alterations that cause loss of tumorsuppressive functions ( 14 ). The promise of paralog targeting in precision cancer medicine has been further validated by the addition of the strategy described here to the previously established repertoire, e.g., the use of SMARCA2/BRMATPase inhibition against SMARCA4/BRG1 -defi cient cancers and ARID1B inhibition against ARID1A-defi cient cancers [19][20][21][22][23]. Thus, the paralog targeting strategy should be applicable to a considerable fraction of human cancers.…”

“…We fi rst demonstrated the feasibility of this strategy by achieving specifi c killing of SMARCA4/BRG1-defi cient cancers through inhibition of the SMARCA4 paralog SMARCA2/BRM-ATPase ( 19 ). These fi ndings were subsequently supported by several studies, including some that employed genome-wide RNA interference scanning (20)(21)(22). Recently, this concept has been extended to ARID1A -defi cient cancers ( 23 ).…”

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

“…These include ARID1A and ARID1B (56), SMARCA2 and SMARCA4 (57), and most recently CBP and EP300 (58). Although the roles of these genes in tumorigenesis are similarly unclear, these examples of synthetic lethality can now be expanded to include UBB, a ubiquitin-encoding gene that serves as a biomarker for a clinically aggressive HGSOC subtype, and its paralog UBC.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…In this regard, mutations that lead to functional loss of some subunits may promote the addiction of tumor cells to the residual complexes to sustain oncogenic growth Helming et al 2014a). In support of this notion, tumors with ARID1A loss show enhanced sensitivity to ARID1B inhibition, and SMARCA4 deficiency induces vulnerability to SMARCA2 targeting (Helming et al 2014b;Hoffman et al 2014;Wilson et al 2014). In addition to such genetically induced "synthetic lethality," mutations of these chromatin modulators also lead to dysfunction of their corresponding pathways, which can be further perturbed by targeted agents.…”