Dataset Information

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

ABSTRACT: Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP^def) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAP^def urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP^def patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP^def patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAP^def associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP^def and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

SUBMITTER: Alhalabi O

PROVIDER: S-EPMC8980015 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

Alhalabi Omar O Chen Jianfeng J Zhang Yuxue Y Lu Yang Y Wang Qi Q Ramachandran Sumankalai S Tidwell Rebecca Slack RS Han Guangchun G Yan Xinmiao X Meng Jieru J Wang Ruiping R Hoang Anh G AG Wang Wei-Lien WL Song Jian J Lopez Lidia L Andreev-Drakhlin Alex A Siefker-Radtke Arlene A Zhang Xinqiao X Benedict William F WF Shah Amishi Y AY Wang Jennifer J Msaouel Pavlos P Zhang Miao M Guo Charles C CC Czerniak Bogdan B Behrens Carmen C Soto Luisa L Papadimitrakopoulou Vassiliki V Lewis Jeff J Rinsurongkawong Waree W Rinsurongkawong Vadeerat V Lee Jack J Roth Jack J Swisher Stephen S Wistuba Ignacio I Heymach John J Wang Jing J Campbell Matthew T MT Efstathiou Eleni E Titus Mark M Logothetis Christopher J CJ Ho Thai H TH Zhang Jianjun J Wang Linghua L Gao Jianjun J

Nature communications 20220404 1

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef</sup ...[more]

PMID: 35379845

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Project description:BackgroundGenetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance.MethodsSanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software.ResultsIn our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient's morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival (p = 0.011) and a shorter progression-free survival (p = 0.016).ConclusionsIt was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.

Dataset Information

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

Publications

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

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