MTAP deletion

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.

Ongoing investigations will be critical to define the therapeutic window of PRMT5 inhibition and to optimize rational combination strategies. This review provides a comprehensive overview of current insights into the oncogenic functions of PRMT5 and highlights emerging therapeutic strategies aimed at improving cancer treatment.

Because MTAP is related to the methionine salvage pathway, various cancer cell lines with MTAP deletion have been reported to exhibit increased sensitivity to the pyrimidine analog 5-fluorouracil (5-FU)...MTAP deficiency is closely associated with homozygous CDKN2A and MTAP deletions in HPV-negative/p16-negative OPSCCs. Furthermore, MTAP loss may be a favorable prognostic factor in HPV-negative OPSCC, and this paradoxical phenomenon might be explained by the enhanced efficacy of chemotherapy with pyrimidine analogs.

In vivo, HBS1L deletion eliminated growth of FOCAD-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treating FOCAD-deleted tumors.

Targeting polyamine biosynthesis reverses IRF3 down-regulation, restoring sensitivity to STING agonists in MTAP-deficient tumors. Our findings suggest that MTAP genetic status may inform patient responses to STING agonist therapy and offer an alternative strategy for boosting antitumor immune responses using STING agonists in MTAP-deleted tumors.

This finding may have implications for the susceptibility of melanoma to PRMT5 and related inhibitors. Methylthioadenosine Phosphorylase (MTAP) and p16 Expression in Melanocytic Nevi and Melanoma with Molecular Correlation.

PRMT5 inhibitors represent a promising therapeutic approach for multiple cancers, but their clinical development is hindered by toxicity to normal cells. Synthetic lethality approaches using MTAP-cooperative PRMT5 inhibitors offer a compelling strategy that selectively targets cancer cells in nerve sheath sarcomas and other MTAP-deleted tumors.

In this perspective, we analyzed the different binding modes between PRMT5·MTA and PRMT5·SAM complexes and highlighted the discovery of the second-generation MTA-cooperative PRMT5 inhibitors with the guidance of their cocrystal structures bound to the PRMT5·MTA complex. We also discussed the challenges and opportunities of these synthetic lethal inhibitors to shed light on future drug development.

PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including exon skipping and intron retention. These results provide new insights into PRMT5's role in splicing regulation and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.

P1/2, N=53, Active, not recruiting, Amgen | Trial completion date: Aug 2025 --> Jan 2026 | Trial primary completion date: Aug 2025 --> Jan 2026

This is the first systematic review to summarize the literature on MTAP deletions or loss of expression across several solid and hematologic cancers. MTAP deletions and/or loss of expression occur in many cancer types, presenting a promising target for pan-cancer therapy.