This emphasizes the importance of considering side effects on the immune system when developing new strategies to specifically target not only MTAP-deficient tumors.
The PRMT5 inhibitor EZP015556, shown to target <i>MTAP</i> (a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors.
While the lack of the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) is associated with methionine auxotrophy in cancer cells, there are other causes for tumors to require exogenous methionine.
It 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.
Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms.
Our results suggest that 2FA+MTA may be a promising combination for treating <i>MTAP</i>-deleted tumors.<b>Significance:</b> Loss of MTAP occurs in about 15% of all human cancers; the MTAP protection strategy presented in this study could be very effective in treating these cancers.<i></i>.
While the lack of the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) deficiency is associated with methionine dependence in cancer cells, there are other causes for tumors to require exogenous methionine.
MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC).
Intriguingly, five CPGs showed concordance between CNL and down-regulation in 50 or more tumor samples: MTAP (216 samples), PTEN (143), MCPH1 (86), SMAD4 (63), and MINPP1 (51), which may represent the recurrent driving force for gene expression change during oncogenesis.
Enzyme assays conducted on the co-dominantly expressed alleles revealed no difference in the conversion rate of MTA to adenine and 5-methylthioribose-1-phosphate, indicating that this known enzymatic activity does not modulate the tumor suppressive function of MTAP.
In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells.
Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors.
Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma.
This gene region houses the CDKN2B/p15(INK4B) , CDKN2A/p16(INK4A) and p14ARF (rat equivalent, p19(ARF) ) tumour suppressor genes and is adjacent to the S-methyl-5'-thioadenosine phosphorylase (MTAP) gene.
The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers.
This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency.
Low MTAP mRNA expression was found in 32% of cases, and was associated with MTAP gene deletion (in 70%; P<0.001) but not with MTAP promoter hypermethylation, indicating that, in this tumour, gene deletion is the main mechanism for MTAP inactivation.