Abstract
SMARCA4 (BRG1) and SMARCA2 (BRM) are the mutually exclusive ATPase subunits of the SWI/SNF chromatin remodeling complexes, often altered in cancers. Concurrent loss of SMARCA4/2 is found in some aggressive cancer types, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare and lethal ovarian cancer affecting young women, and a subset of non-small cell lung cancers (NSCLCs), associated with chemotherapy resistance and poor outcome. Through a functional genetic approach, we identified that inhibition of MCL1, an anti-apoptotic protein of the BCL-2 family, is synthetic lethal with SMARCA4/2 loss in these cancer cells. MCL1 suppression by RNAi or a small molecule inhibitor, S63845, selectively induced apoptosis in SMARCA4/2-deficient SCCOHT and NSCLC cells but not in SMARCA4/2-proficient controls. Mechanistically, SMARCA4/2 directly promotes mRNA expression of BCL-xL, encoding another key anti-apoptotic protein of the BCL-2 family; SMARCA4/2 loss therefore results in downregulation of BCL-xL, leading to MCL1 dependency to suppress apoptosis in these cancer cells. Furthermore, single-agent treatment of S63845 resulted in significant suppression of tumor growth in patient-derived xenografts of SMARCA4/2-deficient NSCLC and SCCOHT. Collectively, our work uncovered MCL1 as a synthetic lethal target in SMARCA4/2-deficient cancers that may be exploited therapeutically.
Data availability
DepMap CRISPR screen: https://depmap.org/portal/. Gene expression/mutation: CCLE (https://portals.broadinstitute.org/ccle), UCSC Xena (http://xena.ucsc.edu/). Drug response: GDSC (https://www.cancerrxgene.org/). Dependency scores: CERES. Public datasets: GSE15102651, GSE11773566, GSE12175525, GSE16261150.
Code availability
All analyses were conducted in R using standard packages for data visualization and statistics. No custom algorithms were developed. The code and analysis scripts are available upon request.
References
Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).
Pan, J. et al. Interrogation of mammalian protein complex structure, function, and membership using genome-scale fitness screens. Cell Syst. 6, 555–568.e557 (2018).
Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009).
Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).
Shain, A. H. & Pollack, J. R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE 8, e55119 (2013).
Tischkowitz, M. et al. Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines. Clin. Cancer Res. 26, 3908–3917 (2020).
Jelinic, P. et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat. Genet. 46, 424–426 (2014).
Ramos, P. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 46, 427–429 (2014).
Witkowski, L. et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. Genet. 46, 438–443 (2014).
Matsubara, D. et al. Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci. 104, 266–273 (2013).
Reisman, D. N., Sciarrotta, J., Wang, W., Funkhouser, W. K. & Weissman, B. E. Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 63, 560–566 (2003).
Estel, R., Hackethal, A., Kalder, M. & Munstedt, K. Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature. Arch. Gynecol. Obstet. 284, 1277–1282 (2011).
Jelinic, P. et al. Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type. Mod. Pathol. 29, 60–66 (2016).
Karnezis, A. N. et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 238, 389–400 (2016).
Karnezis, A. N., Cho, K. R., Gilks, C. B., Pearce, C. L. & Huntsman, D. G. The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nat. Rev. Cancer 17, 65–74 (2017).
Witkowski, L. et al. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type. Gynecol. Oncol. 141, 454–460 (2016).
Xue, Y. et al. SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca(2+) flux to mitochondria. Nat. Commun. 12, 5404 (2021).
Wang, Y. et al. Histone Deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type. Mol. Cancer Ther. 17, 2767–2779 (2018).
Wang, Y. et al. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 242, 371–383 (2017).
Chan-Penebre, E. et al. Selective killing of SMARCA2- and SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type cells by inhibition of EZH2: in vitro and in vivo preclinical models. Mol. Cancer Ther. 16, 850–860 (2017).
Shorstova, T. et al. SWI/SNF-compromised cancers are susceptible to bromodomain inhibitors. Cancer Res 79, 2761–2774 (2019).
Romero, O. A. et al. SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade. Nat. Commun. 12, 4319 (2021).
Lang, J. D. et al. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition. Clin. Cancer Res 24, 1932–1943 (2018).
Xue, Y. et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat. Commun. 10, 558 (2019).
Xue, Y. et al. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat. Commun. 10, 557 (2019).
Ji, J. X. et al. Arginine depletion therapy with ADI-PEG20 limits tumor growth in argininosuccinate synthase-deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-1905 (2020).
Zhu, X. et al. Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss. Nat. Commun. 14, 2894 (2023).
Plati, J., Bucur, O. & Khosravi-Far, R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J. Cell Biochem. 104, 1124–1149 (2008).
Ashkenazi, A., Fairbrother, W. J., Leverson, J. D. & Souers, A. J. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat. Rev. Drug Discov. 16, 273–284 (2017).
Kale, J., Osterlund, E. J. & Andrews, D. W. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 25, 65–80 (2018).
Huang, K. et al. BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. Cell Res 29, 942–952 (2019).
Debrincat, M. A. et al. Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival. Blood 119, 5850–5858 (2012).
Kodama, T. et al. Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages. Cell Death Differ. 19, 1856–1869 (2012).
Perciavalle, R. M. & Opferman, J. T. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 23, 22–29 (2013).
Li, S., Guo, W. & Wu, H. The role of post-translational modifications in the regulation of MCL1. Cell Signal 81, 109933 (2021).
Lee, E. F. & Fairlie, W. D. The Structural Biology of Bcl-xL. Int. J. Mol. Sci. 20 https://doi.org/10.3390/ijms20092234 (2019).
Lewis, A., Hayashi, T., Su, T. P. & Betenbaugh, M. J. Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival. J. Bioenerg. Biomembr. 46, 1–15 (2014).
Plotz, M. et al. Mutual regulation of Bcl-2 proteins independent of the BH3 domain as shown by the BH3-lacking protein Bcl-x(AK). PLoS One 7, e34549 (2012).
Li, M., Wang, D., He, J., Chen, L. & Li, H. Bcl-XL: A multifunctional anti-apoptotic protein. Pharmacol. Res. 151, 104547 (2020).
Williams, M. M. et al. Key Survival Factor, Mcl-1, correlates with sensitivity to combined Bcl-2/Bcl-xL blockade. Mol. Cancer Res. 15, 259–268 (2017).
Wertz, I. E. et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110–114 (2011).
Kotschy, A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538, 477–482 (2016).
Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68, 3421–3428 (2008).
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
Ghandi, M. et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature 569, 503–508 (2019).
Medina, P. P. et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum. Mutat. 29, 617–622 (2008).
Karnezis, A. N. et al. Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines. Gynecol. Oncol. 160, 568–578 (2021).
Yang, W. et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 41, D955–D961 (2013).
Xiang, W., Yang, C. Y. & Bai, L. MCL-1 inhibition in cancer treatment. Onco Targets Ther. 11, 7301–7314 (2018).
Song, S. et al. Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung Carcinoma. Mol. Cancer Res 18, 1777–1788 (2020).
Orlando, K. A. et al. Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism. Elife 9 https://doi.org/10.7554/eLife.59073 (2020).
Stevens, M. & Oltean, S. Modulation of the Apoptosis gene Bcl-x function through alternative splicing. Front Genet 10, 804 (2019).
Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615 (2011).
Zhang, H. et al. Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene 30, 1963–1968 (2011).
Raupach, E. A. et al. Loss of SMARCA4 leads to intron retention and generation of tumor-associated antigens in small cell carcinoma of the ovary, Hypercalcemic Type. Cancer Res 85, 2626–2642 (2025).
Szlavik, Z. et al. Discovery of S64315, a potent and selective Mcl-1 inhibitor. J. Med Chem. 63, 13762–13795 (2020).
Letai, A. S63845, an MCL-1 selective BH3 mimetic: another arrow in our quiver. Cancer Cell 30, 834–835 (2016).
Hellmuth, S. & Stemmann, O. Separase-triggered apoptosis enforces minimal length of mitosis. Nature 580, 542–547 (2020).
Xue, Y. et al. SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors. J. Pathol. 252, 77–87 (2020).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
Le Loarer, F. et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat. Genet. 47, 1200–1205 (2015).
Pan, J. et al. The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting. Nat. Genet. 51, 618–626 (2019).
Acknowledgements
This work was supported by Canadian Institute of Health Research (CIHR) grants PJT-156233 (S.H.), PJT-438303 (S.H.), PJT- 518050 (S.H.), and FDN-148390 (W.D.F). S.H. was supported by a Canada Research Chair in Functional Genomics.
Author information
Authors and Affiliations
Contributions
J.J., X.Z., Z.F., M.L., A.A., A.M., and V.P. carried out experiments and data analysis. J.J. and X.Z. performed statistical and bioinformatic analysis. F.R. and K.P. contributed expertise and samples. M.P., W.D.F., and S.H. supervised the experiments. S.H. conceived and oversaw the study. J.J. and S.H. wrote the manuscript. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Jiang, J., Zhu, X., Fu, Z. et al. SMARCA4/2 loss reduces BCL-xL expression and confers a druggable MCL1 dependency in cancer. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01350-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41698-026-01350-z
