Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Mavrakis, Konstantinos J.; McDonald, Ellice; Schlabach, Michael R.; Billy, Éric; Hoffman, Gregory R.; deWeck, Antoine; Ruddy, David A.; Venkatesan, Kavitha; Yu, Jianjun; McAllister, Gregg; Stump, Mark; DeBeaumont, Rosalie; Ho, Samuel B.; Yue, Yiyang; Liu, Yue; Yan‐Neale, Yan; Yang, Guizhi; Lin, Fallon; Yin, Hong; Gao, Hui; Kipp, D. Randal; Zhao, Songping; McNamara, Joshua T.; Sprague, Elizabeth R.; Zheng, Bing; Lin, Ying; Cho, Young Shin; Gu, Justin; Crawford, Kenneth R.; Ciccone, David N.; Vitari, Alberto C.; Lai, Albert; Čápka, Vladimı́r; Hurov, Kristen E.; Porter, Jeffery A.; Tallarico, John A.; Mickanin, Craig; Lees, Emma; Pagliarini, Raymond; Keen, Nicholas; Schmelzle, Tobias; Hofmann, Francesco; Stegmeier, Frank; Sellers, William R.

doi:10.1126/science.aad5944

Cited by 377 publications

(426 citation statements)

References 31 publications

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“…A s at i s f y i n g example of robustn e s s o c c u r re d when our team published an unexpected finding, one that points to a vulnerability in certain malignancies: cancer cells harbouring a frequent genetic deletion become more reliant on a protein whose activity is regulated by the very metabolite that becomes elevated when the deletion is present. Two other large groups published similar findings at around the same time, each using distinct approaches [16][17][18] . Diverse data that converge on the same observation in aggregate provide robustness, even though any single approach or model system has limitations.…”

Section: Robustnesssupporting

confidence: 56%

Remember why we work on cancer

Garraway

2017

Nature

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Section: Robustnesssupporting

confidence: 56%

Remember why we work on cancer

Garraway

2017

Nature

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“…The chemicals MTA, 3-Deaza and adenosine, were purchased from SigmaAldrich, Aza-CdR was obtained from Biomol/Cayman. The HLA-A2-binding peptide Melan-A [26][27][28][29][30][31][32][33][34][35] (ELAGIGILTV) was prepared by Bachem. Soluble recombinant HCMV pp65 (low endotoxin) was obtained from Miltenyi Biotec.…”

Section: Media Chemicals Cytokines Peptides and Generation Of Denmentioning

confidence: 99%

“…23,24,33 Two recent publications postulate that the loss of MTAP in tumors leads to a heightened susceptibility to a depletion of the methyltransferase PRMT5, as increased intracellular MTA impedes PRMT5 activity. 34,35 Little is known about the effects of MTA on immune cells. Studies suggest an anti-inflammatory effect of MTA, because it inhibits both the secretion of pro-inflammatory cytokines and the activation of the pro-inflammatory transcription factor NF-kB, [36][37][38] as was also shown for T cells.…”

Section: Introductionmentioning

confidence: 99%

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

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The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5 0 -deoxy-5 0 -methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTAcatabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAPcoding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

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“…Finally, increasing efforts to study how deletion and loss-of-function mutations create therapeutic vulnerabilities in relapsed ALL will be important. For example, frequent deletions of the CDKN2A/B locus may also involve deletion of the adjacent gene 5-methylthioadenosine phosphorylase (MTAP) and render cells sensitive to PRTM5 inhibition (10,11). Thus, efforts to link recurrent copy number (CN) changes enriched in ALL relapse, such as CDKN2A/B, IZFK1, and EBF1 deletions, with therapeutic vulnerabilities may be important.…”

mentioning

confidence: 99%

Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

Abdel‐Wahab

2016

Proc. Natl. Acad. Sci. U.S.A.

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Relapsed acute lymphoblastic leukemia (ALL) is associated with very poor outcomes despite modern therapies in both children and adults (1-3). In PNAS, Oshima et al. elucidate both the mutational landscape as well as patterns of clonal evolution of pediatric relapsed ALL and identify potential therapeutic targets in this challenging illness (4). Although prior studies have performed SNP array analysis (SNPa), wholeexome sequencing (WES), whole-genome sequencing (WGS), and/or mRNA sequencing (RNA-seq) at diagnosis and relapse (Table 1), the majority of prior analyses have focused on relapsed pediatric B-ALL specifically. Here, the authors performed WES of 55 pediatric ALL patients (33 T-cell ALL and 22 B-cell precursor ALL) at diagnosis, remission, and relapse and complemented these data with RNA-seq of a validation cohort of 49 paired diagnosis/relapse B-ALL patient samples. This analysis has allowed for reevaluation of the pattern of clonal evolution in relapsed ALL and revealed that the majority of relapsed ALLs (∼85%) contain only some of the genetic lesions present in the major clone at diagnosis. In contrast, only in 4% of cases did the relapsed clones contain all mutations present at diagnosis plus additional secondary relapse-specific lesions. Together, these data identify that linear evolution is rarely involved in tumor progression in ALL and that relapsed ALL originates primarily as derivatives of ancestral subclones related to, but distinct from the main leukemic population present at diagnosis. This conclusion extends previous observations of the clonal basis of relapsed ALL by Mullighan et al. (5), which used SNPa to reveal that cells responsible for relapse were often minor subpopulations of the cells responsible for initial disease (Table 1).In addition to evaluating the clonal basis of relapsed ALL, the authors identified several new genes enriched at relapse including ZFHX3, USP9X, CACNA1H, EPHA3, SHROOM3, USP7, RPGR, HTR3A, MED12, ODZ3, and IL17RA. Mutations associated with relapsed ALL appear to fall into several categories. First, there are mutations functionally related to the mechanism of action of chemotherapy used in initial treatment and/or previously linked to chemotherapy resistance. These include mutations in NT5C2, TP53, NR3C1, CREBBP, and MLL2. Ultradeep sequencing of diagnostic samples failed to identify these mutations in most cases, which suggests they were acquired at relapse and/or present in very small subclones at diagnosis. Given the need to develop novel targeted therapeutics for relapsed ALL, identification of therapeutically targetable genetic alterations enriched in relapse is critical. To this end, prior work from this group and others identified that mutations in the 5′-nucleotidase enzyme NT5C2 enhance inactivation of nucleoside-analog chemotherapeutic agents (6, 7). The frequency of NT5C2 mutations at relapse and the fact that NT5C2 mutations confer enhanced enzymatic activity argue for efforts to develop small-molecule inhibitors of mutant NT5C2.Mutations in CREBBP ...

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Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Cited by 377 publications

References 31 publications

Remember why we work on cancer

Remember why we work on cancer

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

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