Cancer Cancer Research Highlights Research

The Achilles Heel of Malignant Rhabdoid Tumors Jing Huang and Ji Luo

Malignant rhabdoid tumors (MRT) are rare but deadly retain an intact pathway and the authors show that these pediatric tumors characterized by mutations in the cells are particularly sensitive to MDM2 and MDM4 inhibi- SMARCB1/SNF5/INI1/BAF47 . Currently, there are no tion due to SMARCB1's role in regulating p53-depedent targeted therapies for MRTs. In a previous issue of Cancer apoptotic . This discovery suggests potential clinical Research, Howard and colleagues utilize the power of trials of MDM2 inhibitors in patients with MRT. genome-wide RNAi and CRISPR screening to identify MDM2 See related article by Howard and colleagues; Cancer Res 79(9): and MDM4 as potential drug targets for MRTs. Most MRTs 2404–14.

In a previous issue of Cancer Research, Howard and colleagues genome-wide RNAi and CRISPR screens to identify their func- identified MDM2 and MDM4 as drug targets in malignant rhab- tional vulnerabilities (4), the authors discovered that MRT cells doid tumors (MRT; ref. 1). This finding lays a foundation for are particularly sensitive to genetic and pharmacologic suppres- designing effective targeted therapies for this aggressive tumor. sion of MDM2 and MDM4 compared with other cancer cell lines. Malignant rhabdoid tumors (MRT) are rare pediatric tumors that Unlike other solid tumors, the majority of MRTs are wild-type mainly arise in the kidney, brain, or soft tissues (2). Current (WT) for the TP53 tumor suppressor gene and retain a functional treatment options for MRTs are surgery, chemotherapy, and p53 pathway (5, 6). MDM2 and MDM4 are both negative reg- radiation, none of which are particularly effective. Targeted ther- ulators of p53; MDM2 binds to and degrades p53 while MDM4 apies are therefore much needed to improve the survival and sequesters p53 (7). MDM2 and MDM4 amplifications are com- quality of life of patients with MRT. Finding actionable mutations monly seen in human tumors including pediatric tumors such as in MRTs is challenging as recent genome-wide sequencing studies osteosarcoma, however, their genetic alternations are rare in revealed few mutations in these tumors except for loss-of-function MRTs (5, 6). MDM2 and MDM4 also possess p53-independent mutations in the SMARCB1/SNF5/INI1/BAF47 gene (2). activities (7). In their screen, Howard and colleagues also iden- SMARCB1 encodes a core subunit of the mammalian SWI/SNF tified two other negative regulators of p53, PPM1D/WIP1 and complex; subunits of this complex are USP7/TEF1/HAUSP. This suggested that dysregulation of p53 mutated in approximately 20% of all human cancers (3). activity was the underlying mechanism of MDM2 and MDM4 Although SMARCB1 is a bona fide tumor suppressor in MRT, the dependency in MRT cells. Interestingly, they found that MRT cells mechanism by which SMARCB1 deficiency drives MRT is not well are more sensitive to the genetic ablation of these negative understood, however, changes related to cell- regulators of p53 than other TP53 WT cancer cell lines, suggesting cycle dysregulation and stem cell differentiation have been impli- MRTs might be highly sensitive to p53-targeted therapies. Indeed, cated. To date, an important question in the field is how the the authors showed that two structurally unrelated compounds, mutation of SMARCB1, a hallmark of MRT, can be exploited the small-molecule MDM2 inhibitor idasanutlin and the dual therapeutically. MDM2- and MDM4-targeted stapled peptide ATSP-7041, had a To identify targetable vulnerabilities in SMARCB1-mutant greater effect on the viability of MRT cells than other TP53 WT MRTs, Howard and colleagues turned to unbiased RNAi and cancer cell lines. In MRT cells, both inhibitors induced the CRISPR library screening. Loss-of-function screens of this type expression of p53 target genes and deletion of TP53 resulted in are powerful tools for discovering genotype-specific dependencies drug resistance. Thus, the cytotoxicity of these inhibitors is due to in cancer cells. These approaches can identify synthetic lethal the activation of p53 in MRT cells. MDM2 and MDM4 inhibition interactions, which may serve as drug targets, particularly in cancer led to both apoptosis and cell-cycle arrest in MRT cells. Interest- cells that are primarily driven by tumor suppressor loss. Taking ingly, the cytostatic response in some MRT cells was associated advantage of Project Achilles, a large-scale effort that has analyzed with an irreversible, senescent-like phenotype. Thus, activation of hundreds of cancer cell lines from different tissue types with p53 can serve as an effective means to eliminate MRT cells. Mechanistically, Howard and colleagues demonstrated that SMARCB1 loss has an upstream role in the dysregulation of the proapoptotic activity of p53 and this effect appears reversible. The Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. authors restored the expression of SMARCB1 under an inducible promoter in SMARCB1-deficient MRT cells and observed Corresponding Authors: Jing Huang, Center for Cancer Research, National decreased sensitivity to idasanutlin and ATSP-7041. The restora- Cancer Institute, Bethesda, MD 20892. Phone: 240-760-6931; Fax: 301-402-1031; E-mail: [email protected]; and Ji Luo, E-mail: [email protected] tion of SMARCB1 appears to preferentially diminish the effect of these drugs on the induction of proapoptotic p53 target genes Cancer Res 2019;79:2808–9 including BBC3/PUMA and TP53I3/PIG3. It is known that p53 can doi: 10.1158/0008-5472.CAN-19-0990 regulate cell cycle and proapoptotic genes through distinct Ó2019 American Association for Cancer Research. mechanisms. Given that SMARCB1 is a core subunit of the

2808 Cancer Res; 79(11) June 1, 2019

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. SWI/SNF complex, it is possible that this complex, through its pediatric tumors. Together, these results suggest that MDM2 and chromatin remodeling activity, contributes to the differential MDM4 could be an Achilles heel for MRTs. A previous study by regulation of p53 target genes. It remains unclear why SMARCB1 The Pediatric Preclinical Testing Program also found that MDM2 emerges as a dominant tumor suppressor driver in lieu of p53 in inhibitors inhibited the proliferation of MRT cells (9). The study MRT, given that loss of SMARCB1 could sensitize MRT cells by Howard and colleagues has provided both new mechanistic toward p53-induced apoptosis. In other types of cancer, muta- insights into the synthetic lethality between SMARCB1 and the tions in SWI/SNF subunits are also frequently found to be mutu- MDM2–p53 axis and a strong scientific rationale for why MRT ally exclusive with TP53 mutations (8). These observations sug- might be particularly sensitive to MDM2 and MDM4 inhibitors. gest that SWI/SNF and p53 might be regulating the same pathway Idasanutlin is currently being tested in clinical trials for several during tumorigenesis. One speculative idea would be that loss of cancer types but not specifically for MRT. The findings by Howard SWI/SNF activity leads to global chromatin changes that strike a and colleagues warrant further clinical investigation of idasanu- good balance between promoting cell proliferation and shaping tlin and other MDM2 and MDM4 inhibitors in MRT to evaluate cell fate specification (3). This would spare the need for p53 their efficacy in this rare but lethal form of childhood cancer. mutation. However, the fitness cost of such mutational choice would be an increased chromatin accessibility of p53-regulated proapoptotic genes and, consequently, heightened sensitivity to Disclaimer p53-induced cell death. The content is solely the responsibility of the authors and does To explore the translational potential of their findings, Howard not necessarily represent the official views or policies of the and colleagues treated an MRT xenograft model using idasanutlin National Institutes of Health and the Department of Health and and ATSP-7041. Both compounds significantly attenuated tumor Human Services. The mention of trade names, commercial pro- growth and extended survival. Remarkably, idasanutlin caused ducts or organizations does not imply endorsement from the US complete and durable response in half of the mice at a dose that is Government. well tolerated. In tumors treated with either drug, both decreased proliferation and increased apoptosis was observed, although it Disclosure of Potential Conflicts of Interest was unclear whether senescence also contributed to the durable No potential conflicts of interest were disclosed. response. Using a 13-gene signature that is associated with MDM2 sensitivity, the authors showed that human primary MRT samples Received March 25, 2019; revised March 25, 2019; accepted March 26, 2019; scored higher for this signature than both normal tissue and other published first June 1, 2019.

Reference 1. Howard TP, Arnoff TE, Song MR, Giacomelli AO, Wang X, Hong 6. Lee RS, Stewart C, Carter SL, Ambrogio L, Cibulskis K, Sougnez C, et al. A AL, et al. MDM2 and MDM4 are therapeutic vulnerabilities in remarkably simple genome underlies highly malignant pediatric rhabdoid malignant rhabdoid tumors. Cancer Res 2019;79:2404–14. cancers. J Clin Invest 2012;122:2983–8. 2. Geller JI, Roth JJ, Biegel JA. Biology and treatment of rhabdoid tumor. 7. Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer Crit Rev Oncog 2015;20:199–216. therapy. Clin Cancer Res 2013;19:34–41. 3. Helming KC, Wang X, Roberts CWM. Vulnerabilities of mutant SWI/SNF 8. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. complexes in cancer. Cancer Cell 2014;26:309–17. Proteomic and bioinformatic analysis of mammalian SWI/SNF com- 4. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, plexes identifies extensive roles in human malignancy. Nat Genet 2013; et al. Defining a cancer dependency map. Cell 2017;170:564–576.e16. 45:592–601. 5. Chun H-JE, Lim EL, Heravi-Moussavi A, Saberi S, Mungall KL, Bilenky 9. Carol H, Reynolds CP, Kang MH, Keir ST, Maris JM, Gorlick R, M, et al. Genome-wide profiles of extra-cranial malignant rhabdoid et al. Initial testing of the MDM2 inhibitor RG7112 by the pedi- tumors reveal heterogeneity and dysregulated developmental pathways. atric preclinical testing program. Pediatr Blood Cancer 2013;60: Cancer Cell 2016;29:394–406. 633–41.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. The Achilles Heel of Malignant Rhabdoid Tumors

Jing Huang and Ji Luo

Cancer Res 2019;79:2808-2809.

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Cited articles This article cites 9 articles, 2 of which you can access for free at: http://cancerres.aacrjournals.org/content/79/11/2808.full#ref-list-1

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