Skip to main content

MTAP loss: a possible therapeutic approach for glioblastoma


Glioblastoma is the most lethal form of brain tumor with a recurrence rate of almost 90% and a survival time of only 15 months post-diagnosis. It is a highly heterogeneous, aggressive, and extensively studied tumor. Multiple studies have proposed therapeutic approaches to mitigate or improve the survival for patients with glioblastoma. In this article, we review the loss of the 5′-methylthioadenosine phosphorylase (MTAP) gene as a potential therapeutic approach for treating glioblastoma. MTAP encodes a metabolic enzyme required for the metabolism of polyamines and purines leading to DNA synthesis. Multiple studies have explored the loss of this gene and have shown its relevance as a therapeutic approach to glioblastoma tumor mitigation; however, other studies show that the loss of MTAP does not have a major impact on the course of the disease. This article reviews the contrasting findings of MTAP loss with regard to mitigating the effects of glioblastoma, and also focuses on multiple aspects of MTAP loss in glioblastoma by providing insights into the known findings and some of the unexplored areas of this field where new approaches can be imagined for novel glioblastoma therapeutics.


Glioblastoma multiforme (GBM) is the most common and lethal form of brain tumors with a median survival time of approximately 15 months after diagnosis [1]. The prognosis for recovery is very low with a recurrence rate of almost 90%. GBM is a complex disease with tumor heterogeneity, so it is essential to find target genes that can be used for patient specific GBM therapeutics as part of a precision medicine approach. There are several strategies to GBM targeted therapeutics [2]. Previous literature has demonstrated the association of specific gene loss such as loss of MTAP (5′-Methylthioadenosine phosphorylase) and GBM therapeutics [3, 4]. One of the strategies includes combining toxic purine analogs such as 2′-fluoroadenine (2FA) with MTAP substrate, MTA. The 2FA + MTA combination has prohibited the tumor growth in MTAP deleted tumors [5].

MTAP, a tumor suppressor gene, encodes a key rate-limiting metabolic enzyme required for the metabolism of polyamines and purines and has a major function in the purine/methionine salvage pathway [6, 7]. MTAP metabolizes 5’-methylthioadenosine (MTA), generated during polyamine biosynthesis, to produce adenine and methionine and salvages them. Homozygous deletion of MTAP is associated with multiple tumors such as mesothelioma, bladder urothelial carcinoma, pancreatic carcinoma, lung carcinoma, leukemia, and glioma among others [5, 8]. Loss of MTAP expression can be caused by the methylation of the MTAP promoter [9]. The deletion of MTAP has multiple implications. Mutation of MTAP results in dysregulated epigenetics and cancer cell stemness [4]. Based on this functional basis, therapeutic strategies have been developed to target MTAP loss for cancer treatment. Firstly, in MTAP-deficient tumor cells, the absence of the salvage pathway sensitizes cells to inhibitors of de novo purine synthesis and provides an opportunity to specifically target cancer cells. Secondly, MTAP loss results in the accumulation of MTA and this inhibits the activity of several enzymes, including protein arginine methyltransferase 5 (PRMT5). PRMT5 is a regulatory protein critical for multiple processes such as genome organization, cell cycle regulation, and stem cell differentiation [10]. In addition, dysregulation of PRMT5 is associated with multiple cancers and neurological disorders. Deletion of MTAP results in increased dependency on PRMT5 in cancer cells thus providing the potential avenues for targeted therapies [11]. Besides PRMT5, the vulnerability is also noticed in other upstream and downstream enzymes of PRMT5 including methionine adenosyltransferase II alpha (MAT2A) and Rio domain containing protein (RIOK1) [12].

Although MTAP is functionally relevant in several tumors, MTAP has not been studied extensively and this is evident from the number of published papers in literature databases e.g. PubMed. Keyword search in PubMed for “MTAP” affords only 455 articles to date (PubMed accessed on May 4, 2022, search for “Methylthioadenosine phosphorylase” resulted in 450 articles, and search for “MTAP” and “glioblastoma” resulted in 23 articles. However, the search for “Methylthioadenosine phosphorylase” and “glioblastoma” resulted in only 12 articles of which three were reviews but notably there was no review article specifically on MTAP to date. In this article, we review MTAP with a particular focus on its loss among different tumors and how MTAP loss may be relevant as a therapeutic approach for glioblastoma. In addition, we have also reviewed the relevance of MTAP in other cancers, specific inhibitors, and the associated clinical trials.

MTAP metabolism pathway

In normal cells, MTAP metabolizes 5’-Methylthioadenosine (MTA), a by-product of polyamine biosynthesis, to produce adenine and 5-methylthioribose-1-phosphate (MTR-1-P) [13]. MTR-1-P is converted to methionine by utilizing a series of intermediate steps, and adenine is converted to adenosine 5′-monophosphate (AMP) by utilizing adenine phosphoribosyltransferase (APRT). AMP is also produced by de novo purine biosynthesis (Fig. 1). Adenosine triphosphate (ATP) is generated from AMP providing cell energy.

Fig. 1
figure 1

MTAP metabolism pathway. MTAP metabolizes MTA to produce adenine and methionine utilizing a series of intermediate steps. Loss of MTAP (shown by a bold red cross) results in accumulation of MTA and this inhibits PRMT5. Methionine which gets salvaged by MTAP and also can be generated by the folate metabolism pathway is the core of the salvage pathway and the recycle pathway. Methionine gets converted to SAM by MAT2A and SAM can be converted to either MTA or SAH resulting in the salvage and the recycle pathway respectively. AG-270 inhibits MAT2A and this results in lower levels of SAM and thus slows the growth of tumor cells. MTAP is a significant metabolic enzyme because of its involvement in multiple important cellular processes such as protein synthesis, purine synthesis among others as shown in blue. Single step conversions are shown as solid arrows and conversions requiring multiple steps are shown as dashed arrows

Hence, in MTAP-deficient cells, adenine is not produced from MTA. As a result, for AMP production, cells completely rely on de novo purine biosynthesis. Also, cells become more sensitive to inhibitors of de novo purine biosynthesis [14, 15] and methionine starvation [9]. These inhibitors include L-alanosine, 6-mercaptopurine, 6-thioguanine (6-TG). This phenomenon is used for selective killing of MTAP deleted cells. The cells are treated with MTA, followed by a high dose of purine analogs like L-alanosine or 6-TG. In normal cells, adenine blocks the conversion of the analog to its toxic nucleotide by phosphoribosylation with 5-phosphoribosyl-1-pyrophosphate (PRPP). However, in MTAP deleted cells, due to lack of adenine, PRPP is present at a high level and converts the analog to its toxic nucleotide, hence killing the tumor cell [16] (Fig. 1).

On the other hand, polyamine biosynthesis connects methionine cycle and one-carbon metabolism [17]. Decarboxylation of s-adenosyl-methionine (SAM) removes one-carbon unit from the methionine cycle. It produces polyamines and MTA. MTA carries the one-carbon unit. With the help of folate derivatives, the one-carbon unit returns back to the methionine cycle for further synthesis of methionine and SAM [18]. Thus MTAP pathway is linked to the folate metabolism pathway through the core component methionine [19, 20] and opens up the possibility of antifolate therapy in treating GBM [21].

Impact of MTAP loss in GBM

The gene encoding MTAP is located adjacent to cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and CDKN2B-AS1 in the genomic locus 9p21.3. MTAP loss is associated with the deletion of CDKN2A in the 9p21 locus [22, 23]. MTAP deletion is prevalent in approximately 15% of all solid tumors [20]. In gliomas, deletion of the 9p21 is more frequent in grade IV glioma as compared to grade I glioma [24]. Based on the microarray analysis, Suzuki et al. have shown that MTAP is one of the most frequently deleted genes in glioblastoma [25]. Across 32 TCGA PanCancer Atlas studies, data accessed using cBioPortal [26, 27], MTAP loss is the maximum in GBM based on alteration frequency (deep deletion) and GBM has the maximum alteration frequency for deep deletion (> 40% of the cases); in terms of RNA expression data, GBM has the least median expression for MTAP. Besides GBM, MTAP loss is seen in a wide variety of cancers including mesothelioma, bladder urothelial carcinoma, and pancreatic carcinoma among others, and MTAP is also considered as a tumor suppressor gene [7, 28]. MTAP loss in GBM has its impact on multiple aspects—co-deletion of CDKN2A, prognosis, metabolism pathway, immunosuppressive profile, and cancer cell stemness [4] among others.

Co-deletion of MTAP and CDKN2A in GBM

MTAP is frequently co-deleted with CDKN2A in a wide variety of cancers such as malignant pleural mesothelioma [29, 30], non-small cell lung cancer [30, 31], and gliomas [32, 33]. Apart from reporting MTAP as most frequently deleted gene, Suzuki et al. have also shown that MTAP and CDKN2A are co-deleted in 15 cases accounting for 50% of the total glioblastoma cases analyzed [25]. GBM, and lower grade glioma (LGG) datasets have shown that MTAP and CDKN2A are co-deleted in more than 40% of the cases in GBM; however, the co-deletion occurs in approximately 8% of the cases in LGG, which include astrocytoma, oligoastrocytoma and oligodendroglioma. GBM had the least expression for both MTAP and CDKN2A compared to LGG. Also, the expression correlation of MTAP and CDKN2A is higher in GBM compared to LGG, being almost twice as highly correlated in GBM.

Genetic alteration and reduced expression of MTAP in GBM

Homozygous deletion of MTAP is one of the most frequent genetic alterations in GBM. In gliomas, loss of MTAP expression is associated with 9p21 locus deletion and as shown based on the data in cBioPortal it is often co-deleted with CDKN2A in many cancers. Analysis of copy number alteration in the TCGA-GBM dataset by Menezes et al. [7] has shown that there was significantly lower MTAP gene expression in the homozygous deleted group compared to the normal (p < 0.01). Also based on the glioma subtype analysis, they have shown that all the subtypes showed more than 50% MTAP gene expression loss except for the G-CIMP (Glioma-CpG Island Methylator Phenotype) subtype, and the classical subtype showed the highest frequency of loss of MTAP gene expression. It is reported that G-CIMP + subtypes usually co-occur with IDH mutation and have better prognosis [34]. According to the stratified analysis based on different grades of glioma, MTAP expression loss in the high-grade glioma subgroup was almost two-fold greater than in the lower-grade glioma subgroup, although there was no association between MTAP expression and clinicopathological features of patients such as gender and age. Interestingly and contrary to other authors, Menezes et al. have shown that reduced MTAP expression, which is a result of higher MTAP loss frequency in GBM, is associated with better prognosis in adult glioblastoma; although MTAP loss does not affect cell line proliferation, invasion, and migration as shown in their study results based on in vitro models [7]. Menezes et al. further showed that MTAP does not have strong biological importance in gliomas using in silico and in vitro models. Moreover, they have shown that MTAP neither has a clinical impact on gliomas nor does it act as a canonic tumor suppressor gene [7]. Based on the TCGA-GBM data analysis, the results of the study have shown that the loss of MTAP expression is due to its loss and not due to its promoter methylation. This is unlike the findings of another study by Hansen et al. [4] that showed an association of MTAP methylation and loss of expression although with a low coefficient of correlation. It is also to be noted that MTAP loss is not observed in some cancers like prostate cancer [18]. Additional studies may be required to explore this aspect in further detail.

MTAP loss and immunosuppressive profile in GBM

Previous studies [35, 36] have shown that GBM cells utilize multiple strategies to escape the immune surveillance and create an immunosuppressive environment. Hence GBM is characterized by its immunosuppressive nature. MTAP loss results in the accumulation of MTA. The metabolite MTA is associated with cellular context-dependent mechanisms such as targeting the Akt signal pathway, downregulation of TNFα response and host inflammatory response among other associations. Hansen et al. investigated the link between MTAP loss and GBM microenvironment and has shown that loss of MTAP correlates with an immunosuppressive profile in GBM [3]. The results of the study also showed that MTAP loss correlates with differential expression of genes regulating innate or adaptive immune response in experimental cell models and in GBM samples as well. Specifically, MTAP null cells showed lower expression of HLA genes and reduced expression of inflammatory cytokines.

Also, low MTAP expression affects immunosuppressive molecular profiles and has correlations with different immune cells. These correlations manifest in several ways, including alteration in immune cell populations, such as higher M2 macrophages, decreased proportions of γδT cells, and fewer activated CD4 cells which indicates the immunosuppressive context. The study by Hansen et al. concludes with the suggestion that MTAP loss contributes to an immunosuppressive microenvironment in GBM cells. MTAP status should be an important consideration when exploring the immune states and devising immunotherapy-based approaches for GBM treatment.

MTAP loss promotes cancer cell stemness in GBM

Hansen et al. have shown that a deficiency in MTAP influences the DNA methylome by dysregulation of glioma cell epigenome and promotion of “stemness” in GBM cells [4]. MTAP deficiency leads to increased expression of PROM1/CD133 which results in enhanced tumorigenicity of GBM cells and also promotes glioma stem-like cell (GSC) formation. This is associated with poor prognosis in GBM patients. Although expression of CD133 is associated with poor clinical outcomes in GBM patients and PROM1 expression is required for defining stem cells giving rise to cancer, there are additional markers as well that are identified for different cellular features including cellular characteristics, origins and hierarchy. The results of the study by Hansen et al. support that MTAP loss contributes to the genesis and/or maintenance of the stem-like cancer cells and also regulates specific characteristics of these cells in GBM pathogenesis. These results provide evidence for the role of MTAP loss in GBM pathogenesis, as they have shown that MTAP loss is at the core of the two main components of GBM pathogenesis, which are aberrant DNA methylation, a key feature of cancer cells, and the GBM cell stemness. The findings of this study support and reveal a significant concept of linking aberrant metabolism leading to epigenetic alterations in tumor cells [37, 38]. Since GBM pathogenesis is promoted by MTAP loss, this provides a unique opportunity for GBM therapeutics. Hansen et al. suggest that purine deprivation-based therapy may be a unique approach for the treatment of MTAP-null GBM as they are vulnerable to purine starvation [4].

MTAP loss in pediatric glioma

Different studies have shown varying results for MTAP loss in pediatric glioma. Based on glioma cell line data, Menezes et al. have shown that there is no loss of MTAP expression in pediatric GBM cell lines, which is in contrast to 50% of cell lines showing loss of MTAP expression in adult glioma cell lines [7]. However, Frazao et al. have shown deletion of MTAP in pediatric gliomas [32]. Frazao et al. also suggested that co-deletion of MTAP and CDKN2A may have therapeutic relevance in pediatric glioma. Further research is required to find additional details and also study the impact of MTAP loss in the context of pediatric glioma. This will facilitate targeted therapy approaches in pediatric glioma as well.

Relevance of MTAP loss in other cancers

Besides glioblastoma, MTAP loss is also relevant in multiple other cancers as shown across 32 TCGA PanCancer Atlas Studies, data accessed using cBioPortal. Furthermore, MTAP loss is also significant in rare tumors such as chordoma. Chordoma is a rare, aggressive and invasive cancerous tumor of the bone involving the base of the skull, spine and sacrum [39]. Chordoma cases have poor prognosis and are a part of a major group of bone and soft tissue tumors called sarcomas. Previously published studies have shown that MTAP loss has implications on chordoma [28, 40]. Other studies have also shown the association of MTAP with different cancers such as head and neck carcinoma [41], lung cancer [42], prostate [18], colorectal [43], and breast cancer [44]. Even though MTAP is associated with several cancers, the functional relevance and the biological mechanism are yet to be fully understood [45].

Inhibitors for targeted therapy

There have been only a few inhibitors that are currently undergoing clinical trials in the context of MTAP. In this section, we have reviewed these specific inhibitors, and relevant clinical trials for the drugs and/or inhibitors in the context of MTAP are listed in Table 1.

Table 1 Clinical trials in the context of MTAP. Data collected from on 14th May 2022

Methionine adenosyltransferase II alpha (MAT2A) is expressed in most tissues and cancer cells and is a key enzyme that utilizes methionine to produce S-adenosyl methionine (SAM) in both normal and cancer cells (Fig. 1) [46]. SAM is converted back to MTA completing the cycle (Fig. 1). AG-270 is a safe, tolerable and first-in-class oral MAT2A inhibitor that reduces the proliferation of cancer cells and tumors that lack MTAP [47]. AG-270, currently undergoing a clinical trial (NCT03435250), has been shown to inhibit MAT2A thus blocking the conversion of methionine to SAM and reducing SAM production to a lower level compared to normal. Consequently, the reduction of SAM levels slows down the growth of the cancer cells. The growth of MTAP-deleted cancer cells is blocked as a result of MAT2A inhibition which lowers PRMT5-dependent mRNA splicing and prompts DNA damage [20]. Tumors that have MTAP and p16 co-deletion are sensitive to inhibition of MAT2A and that makes MAT2A an attractive lethal target for MTAP-deleted cancers.

IDE397 is another MAT2A inhibitor that is currently being evaluated in a clinical trial (NCT04794699). IDE397 is a differentiated small molecule inhibitor with great potential for MTAP-deleted cancer patients. IDE397 has demonstrated single-agent anti-tumor activity across various solid tumors including non-small cell lung cancer, gastric and bladder cancer among others.

Besides AG-270 and IDE397 which inhibit MAT2A, in the clinical trial NCT03666988, Fedoriw et al. have shown GSK3368715 as a potential type I PRMT inhibitor [48]. The deficiency of MTAP results in impaired PRMT5 activity and thus sensitizes cancer cells to GSK3368715. To inhibit tumor growth, GSK3368715 works synergistically with PRMT5 inhibitor, GSK3326595. GSK3368715 works by altering exon usage and has strong anti-cancer activity. MTAP loss results in accumulation of PRMT5 inhibitor and this correlates sensitivity to GSK3368715.

Falchook et al. have used PRT811, another PRMT5 inhibitor for treating advanced gliomas. PRT811 is a molecule which worked as a potent, selective brain penetrant PRMT5 inhibitor in animal models of brain tumors [49]. In the clinical trial (NCT04089449), Falchook et al. observed tolerance of PRT811. The inhibition of PRMT5 and anti-tumor activity was observed after multiple doses of PRT811 [50].

AMG 193 is another PRMT5 inhibitor which preferentially binds with MTA-bound state of PRMT5 which is abundant in MTAP-deficient tumors. Clinical trial NCT05094336 uses AMG 193 to check efficacy in advanced MTAP-null solid tumors [51].

TNG908 is also a PRMT5 inhibitor and is being orally administered in the clinical trial NCT05275478 to treat MTAP-deleted advanced solid tumors. TNG908 can bind with PRMT5-MTA complex leading selective inhibition of PRMT5 in MTAP-deleted tumors [52].

MRTX1719 is another inhibitor which targets PRMT5-MTA complex and inhibits PRMT5 activity in animal model of MTAP-deleted tumors [53]. It is being tested in human subjects in the clinical trial NCT05245500.

MTA together with 6-thiogunaine (6-TG) provides selective treatment for cancers with MTAP loss [54]. Therapeutic effects utilizing 6-TG may also be enhanced in MTAP-deficient tumors, when combined with other agents such as methotrexate or pralatrexate. Pemetrexed is an anti-folate drug that inhibits nucleic acid synthesis and disrupts folate-dependent metabolic processes required for cell replication. Pemetrexed also inhibits multiple other enzymes such as thymidylate synthase (TS) and glycinamide ribonucleotide formyl transferase (GARFT) among others in the folate pathway and hence has more clinical significance compared to methotrexate. Several clinical trials are on-going which use Pemetrexed for different types of cancers like chordoma (NCT03955042), and MTAP deficient urothelial cancer (NCT03744793, NCT05335941).

Clinical trials having NCT identifiers NCT00062283 and NCT00075894 use anitibiotic l-alanosine as an inhibitor for MTAP-deficient tumor cells. L-alanosine inhibits purine synthesis by blocking de novo purine synthesis pathway [55]. These trials were initiated in 2003 and 2004, however no results were posted at the time of writing this review.


MTAP loss has shown potential to create novel GBM therapeutics according to a number of studies; however, Menezes et al. [7] suggest otherwise. Given the lack of clarity regarding the utilization of MTAP deficiency, more studies are warranted to determine the therapeutic potential of MTAP deficiency. This opens new avenues for research in the context of MTAP deficit in cancers including both GBM and lower grade glioma. Palanichamy et al. [56] have shown that methionine and MTA are among differentially regulated metabolites in GBM cells, unlike normal human astrocytes. Also, GBM cells depend on dietary methionine for cell proliferation, colony formation and survival. The results of the study by Palanichamy et al. suggested that the differentially regulated metabolites and their respective pathways serve as potential therapeutic targets for GBM. Interestingly, Barekatain et al. [33] have shown that MTA does not significantly accumulate in vivo because MTA is metabolized by MTAP-expressing stroma; and this leads to metabolic discrepancies in MTA accumulation between in vitro models and primary human tumors. Therefore, this discrepancy must be taken into consideration when precision therapies are being developed for glioblastoma with homozygous MTAP deletion. Moreover, the CDKN2A/MTAP deletion is mostly observed in higher grade glioma [33] and hence tumors at early stage cannot be treated by solely targeting MTAP loss. Any therapeutic approach based on MTAP loss will be applicable to a subgroup of patients. In some rare cases associated with non-small-cell lung cancer and some other cancers MTAP loss occurred in absence of CDKN2A deletion [57]. In such cases targeting MTAP loss may be challenging.

Availability of data and materials

Not applicable.



Methylthioadenosine phosphorylase




Adenosine 5′-monophosphate


Adenosine triphosphate


S-adenosyl methionine


S-adenosyl homocysteine


Methionine adenosyltransferase II alpha


Adenine phosphoribosyltransferase


Protein arginine methyltransferase 5




Methyl tetrahydrofolate


  1. Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pacific J Cancer Prev. 2017;18(1):3–9.

    Google Scholar 

  2. Taylor OG, Brzozowski JS, Skelding KA. Glioblastoma multiforme: an overview of emerging therapeutic targets. Front Oncol. 2019;8;963.

    Article  Google Scholar 

  3. Hansen LJ, Yang R, Woroniecka K, Chen L, Yan H, He Y. MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization. Sci Rep. 2022;12:4183.

    Article  CAS  Google Scholar 

  4. Hansen LJ, Sun R, Yang R, Singh SX, Chen LH, Pirozzi CJ, et al. MTAP loss promotes stemness in glioblastoma and confers unique susceptibility to purine starvation. Cancer Res. 2019;79(13):3383–94.

    Article  CAS  Google Scholar 

  5. Tang B, Lee HO, An SS, Cai KQ, Kruger WD. Specific targeting of MTAP-deleted tumors with a combination of 2′-fluoroadenine and 5′-methylthioadenosine. Cancer Res. 2018;78(15):4386.

    Article  CAS  Google Scholar 

  6. Savarese TM, Crabtree GW, Parks RE. 5′-methylthioadenosine phosphorylase—I: substrate activity of 5′-deoxyadenosine with the enzyme from sarcoma 180 cells. Biochem Pharmacol. 1981;30(3):189–99.

    Article  CAS  Google Scholar 

  7. de Menezes WP, Silva VAO, Gomes INF, Rosa MN, Spina MLC, Carloni AC, et al. Loss of 5′-methylthioadenosine phosphorylase (MTAP) is frequent in high-grade gliomas; nevertheless, it is not associated with higher tumor aggressiveness. Cells. 2020;9(2):492.

    Article  Google Scholar 

  8. Hustinx SR, Hruban RH, Leoni LM, Iacobuzio-Donahue C, Cameron JL, Yeo CJ, et al. Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy. Cancer Biol Ther. 2005;4(1):83–6.

    Article  CAS  Google Scholar 

  9. Bertino JR, Waud WR, Parker WB, Lubin M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: Current strategies. Cancer Biol Ther. 2011;11(7):627.

    Article  CAS  Google Scholar 

  10. Stopa N, Krebs JE, Shechter D. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell Mol Life Sci. 2015;72(11):2041–59.

    Article  CAS  Google Scholar 

  11. Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016;351(6278):1214–8.

    Article  CAS  Google Scholar 

  12. Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep. 2016;15(3):574–87.

    Article  CAS  Google Scholar 

  13. Lubin M, Lubin A. Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy. PLoS One. 2009;4(5);e5735. 

    Article  Google Scholar 

  14. Ruefli-Brasse A, Sakamoto D, Orf J, Rong M, Shi J, Carlson T, et al. Methylthioadenosine (MTA) rescues methylthioadenosine phosphorylase (MTAP)-deficient tumors from purine synthesis inhibition in vivo via non-autonomous adenine supply. J Cancer Ther. 2011;2:523–34.

    Article  CAS  Google Scholar 

  15. Li WW, Su D, Mizobuchi H, Martin DS, Gu B, Gorlick R, et al. Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells. Oncol Res. 2004;14(7–8):373–9.

    Article  CAS  Google Scholar 

  16. He HL, Lee YE, Shiue YL, Lee SW, Chen TJ, Li CF. Characterization and prognostic significance of methylthioadenosine phosphorylase deficiency in nasopharyngeal carcinoma. Med. 2015;94(49):1–11.

    Google Scholar 

  17. Ghannad-Zadeh K, Das S. One-carbon metabolism associated vulnerabilities in glioblastoma: a review. Cancers. 2021;13(12):3067.

    Article  CAS  Google Scholar 

  18. Bistulfi G, Affronti HC, Foster BA, Karasik E, Gillard B, Morrison C, et al. The essential role of methylthioadenosine phosphorylase in prostate cancer. Oncotarget. 2016;7(12):14380–14393.

    Article  Google Scholar 

  19. Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer. 2019;19:625–637.

    Article  CAS  Google Scholar 

  20. Kalev P, Hyer ML, Gross S, Konteatis Z, Chen CC, Fletcher M, et al. MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage. Cancer Cell. 2021;39(2):209-24.e11.

    Article  CAS  Google Scholar 

  21. Alhalabi O, Chen J, Zhang Y, Lu Y, Wang Q, Ramachandran S, et al. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers. Nat Commun 2022; 13(1):1797.

    Google Scholar 

  22. Han G, Yang G, Hao D, Lu Y, Thein K, Simpson BS, et al. 9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy. Nat Commun. 2021;12(1):5606.

    Article  CAS  Google Scholar 

  23. Olopade OI, Jenkins RB, Ransom DT, Malik K, Pomykala H, Bobori T, et al. Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas. Cancer Res. 1992;1(52):2523–9.

    Google Scholar 

  24. Wemmert S, Ketter R, Rahnenführer J, Beerenwinkel N, Strowitzki M, Feiden W, Hartmann C, Lengauer T, Stockhammer F, Zang KD, Meese E, Steudel WI, von Deimling A, Urbschat S. Patients with high-grade gliomas harboring deletions of chromosomes 9p and 10q benefit from temozolomide treatment. Neoplasia. 2005;7(10);883-893. 

    Article  CAS  Google Scholar 

  25. Suzuki T, Maruno M, Wada K, Kagawa N, Fujimoto Y, Hashimoto N, et al. Genetic analysis of human glioblastomas using a genomic microarray system. Brain Tumor Pathol. 2004;21;27-34.

    Article  CAS  Google Scholar 

  26. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.

    Article  Google Scholar 

  27. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269);pl1.

    Article  Google Scholar 

  28. Bertino JR, Waud WR, Parker WB, Lubin M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol Ther. 2011;1(7);627-632. 

    Article  CAS  Google Scholar 

  29. Illei PB, Rusch VW, Zakowski MF, Ladanyi M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res. 2003;9(6):2108–13.

    CAS  Google Scholar 

  30. Grard M, Chatelain C, Delaunay T, Pons-Tostivint E, Bennouna J, Fonteneau JF. Homozygous co-deletion of type I interferons and CDKN2A genes in thoracic cancers: potential consequences for therapy. Front Oncol. 2021;11;695770.

    Article  Google Scholar 

  31. Su CY, Chang YC, Chan YC, Lin TC, Huang MS, Yang CJ, et al. MTAP is an independent prognosis marker and the concordant loss of MTAP and p16 expression predicts short survival in non-small cell lung cancer patients. Eur J Surg Oncol. 2014;40(9);1143-1150.

    Article  Google Scholar 

  32. Frazão L, Do Carmo Martins M, Nunes VM, Pimentel J, Faria C, Miguéns J, et al. BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - markers in the clinical stratification of pediatric gliomas. BMC Cancer. 2018;18(1):1259.

    Article  Google Scholar 

  33. Barekatain Y, Ackroyd JJ, Yan VC, Khadka S, Wang L, Chen KC, et al. Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine. Nat Commun. 2021;12(1):4228.

    Article  CAS  Google Scholar 

  34. Malta TM, De Souza CF, Sabedot TS, Silva TC, Mosella MS, Kalkanis SN, et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol. 2018;20(5):608-620.

    Article  CAS  Google Scholar 

  35. Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17;vii9-vii14.

    Article  CAS  Google Scholar 

  36. Woroniecka K, Chongsathidkiet P, Rhodin K, Kemeny H, Dechant C, Harrison Farber S, et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin Cancer Res. 2018;24(17):4175–86.

    Article  CAS  Google Scholar 

  37. Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metabol. 2012;16(1):9–17.

    Article  CAS  Google Scholar 

  38. Kaelin WG, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153:56–69.

    Article  CAS  Google Scholar 

  39. Walcott BP, Nahed BV, Mohyeldin A, Coumans JV, Kahle KT, Ferreira MJ. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69-76.

    Article  Google Scholar 

  40. Sommer J, Itani DM, Homlar KC, Keedy VL, Halpern JL, Holt GE, et al. Methylthioadenosine phosphorylase and activated insulin-like growth actor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol. 2010;220(5):608–17.

    Article  CAS  Google Scholar 

  41. Basu I, Cordovano G, Das I, Belbin TJ, Guha C, Schramm VL. A transition state analogue of 5′-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers. J Biol Chem. 2007;282(29):21477–86.

    Article  CAS  Google Scholar 

  42. Basu I, Locker J, Cassera MB, Belbin TJ, Merino EF, Dong X, et al. Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5′-methylthioadenosine phosphorylase. J Biol Chem. 2011;286(6):4902–11.

    Article  CAS  Google Scholar 

  43. Zhong Y, Lu K, Zhu S, Li W, Sun S. Characterization of methylthioadenosin phosphorylase (MTAP) expression in colorectal cancer. Artif cells. Nanomed Biotechnol. 2018;46(8):2082–7.

    CAS  Google Scholar 

  44. Jeon H, Kim JH, Lee E, Jang YJ, Son JE, Kwon JY, et al. Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo. Oncotarget. 2016;7(41):67223–34.

    Article  Google Scholar 

  45. Casero RA, Murray Stewart T, Pegg AE. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat Rev Cancer. 2018;18(11):681–695.

    Article  CAS  Google Scholar 

  46. De Fusco C, Schimpl M, Börjesson U, Cheung T, Collie I, Evans L, et al. Fragment-based design of a potent MAT2a inhibitor and in vivo evaluation in an MTAP null xenograft model. J Med Chem. 2021;64(10):6814–26.

    Article  Google Scholar 

  47. Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, et al. Discovery of AG-270, a first-in-class oral MAT2A inhibitor for the treatment of tumors with homozygous MTAP deletion. J Med Chem. 2021;64(8):4430–49.

    Article  CAS  Google Scholar 

  48. Fedoriw A, Rajapurkar SR, O’Brien S, Gerhart SV, Mitchell LH, Adams ND, et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, Synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell. 2019;36(1):100–14.e25.

    Article  CAS  Google Scholar 

  49. Zhang Y, Lin H, Wang M, Angelis D, Hawkins M, Rominger D, et al. Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors. In: Proceedings of the Annual Meeting of the American Association for Cancer Research. Philadelphia: American Association for Cancer Research; 2020. p. 2919.

  50. Falchook GS, Glass J, Monga V, Giglio P, Mauro D, Viscusi J, et al. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics. Philadelphia, USA: American Association for Cancer Research; 2021.

  51. Villalona-Calero MA, Patnaik A, Maki RG, O’Neil B, Abbruzzese JL, Dagogo-Jack I, et al. Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors. J Clin Oncol. 2022;40(16_suppl);TPS3167–TPS3167.

    Article  Google Scholar 

  52. Briggs KJ, Cottrell KM, Tonini MR, Wilker EW, Gu L, Davis CB, et al. TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022. American Association for Cancer Research; 2022. p. 3941–3941.

  53. Smith CR, Aranda R, Bobinski TP, Briere DM, Burns AC, Christensen JG, et al. Fragment-based discovery of MRTX1719, a synthetic lethal inhibitor of the PRMT5•MTA complex for the treatment of MTAP-deleted cancers. J Med Chem. 2022;10(3):1749–66.

    Article  Google Scholar 

  54. Munshi PN, Lubin M, Bertino JR. 6-Thioguanine: a drug with unrealized potential for cancer therapy. Oncologist. 2014;19(7):760–5.

    Article  CAS  Google Scholar 

  55. Singh SX, Yang R, Roso K, Hansen LJ, Du C, Chen LH, et al. Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells. Biomedicines. 2022;10(4):751.

    Article  CAS  Google Scholar 

  56. Palanichamy K, Thirumoorthy K, Kanji S, Gordon N, Singh R, Jacob JR, et al. Methionine and kynurenine activate oncogenic kinases in glioblastoma, and methionine deprivation compromises proliferation. Clin Cancer Res. 2016;22(14):3513–23.

    Article  CAS  Google Scholar 

  57. Marjon K, Kalev P, Marks K. Cancer dependencies: PRMT5 and MAT2A in MTAP/p16-deleted cancers. Annu Rev Cancer Biol. 2021;5:371–90.

    Article  Google Scholar 

Download references


Not applicable.


Not applicable.

Author information

Authors and Affiliations



CPKP has written the manuscript. NB has revised the manuscript. All the co-authors have read, edited as required and approved the final version of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Nupur Biswas.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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 The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patro, C.P.K., Biswas, N., Pingle, S.C. et al. MTAP loss: a possible therapeutic approach for glioblastoma. J Transl Med 20, 620 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: