MTAP deletion

Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.

P1, N=60, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P1/2, N=110, Terminated, Tango Therapeutics, Inc. | N=192 --> 110 | Active, not recruiting --> Terminated; Sponsor Decision - Business Decisions

P1, N=169, Active, not recruiting, IDEAYA Biosciences | Recruiting --> Active, not recruiting

Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies.

Emerging immunotherapies targeting Claudin18.2 and CXCR4 offer hope to overcome tumor resistance. Together, these strategies underscore the promise of molecular stratification, synthetic lethality, and novel targets to improve pancreatic cancer survival.

MTAP loss is frequent in oncogene-driven NSCLC, particularly in ALK-, RET-, and EGFR-altered subtypes. MTA-cooperative PRMT5 inhibition demonstrates broad activity in MTAP-deleted, oncogene-driven models and, and may enhance targeted therapy efficacy in selected settings.

MTAP activity was also measured across a panel of cancer cell lines to determine intracellular MTAP levels and to complement whole-blood measurements. This approach enables real-time evaluation of MTAP function and drug response in μL volumes of lysate, providing a direct biological or clinical platform for tracking targeted MTAP therapies.

Discordant CDKN2A/B and MTAP tumors affect the association between MTAP IHC and copy number status of MTAP and CDKN2A/B. These findings suggest that adult-type diffuse gliomas, regardless of IDH status, follow a stereotypic pathway involving concurrent CDKN2A/B and MTAP heterozygous deletion but may diverge for CDKN2A/B and MTAP homozygous deletion.

P2, N=60, Suspended, M.D. Anderson Cancer Center | Not yet recruiting --> Suspended

P1, N=36, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Jun 2026 --> Feb 2026