MTAP deletion

Xenograft studies using MTAP- HT1080 and MiaPaCa-2 cell lines have shown that a 2FA/MTA/FX cocktail can cause tumor regression in vivo . These studies suggest that the combination of 2FA/MTA/FX should be explored as a treatment for MTAP- cancer.

About 20% of hepatobiliary carcinomas showed MTAP expression loss, which may benefit from MTAP-directed therapies. MTAP expression loss may be a diagnostic marker for malignant hepatobiliary tumors. MTAP-deleted CCAs and cHCC-CCAs may represent a distinct group of hepatobiliary tumors.

Comprehensive genomic profiling is essential for patients with PAAD and carries both prognostic and predictive value. MTAP loss KRAS-mutant PAAD represents a subgroup of immune-excluded PAADs with a poor prognosis.

P2/3, N=470, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.

P1, N=120, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=350 --> 120 | Trial completion date: Feb 2029 --> Nov 2026 | Trial primary completion date: Feb 2027 --> Oct 2026

P2, N=61, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=200 --> 61 | Trial completion date: Nov 2030 --> Nov 2026 | Trial primary completion date: Nov 2028 --> Oct 2026

P1, N=49, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=500 --> 49 | Trial completion date: Oct 2031 --> Nov 2026 | Trial primary completion date: Oct 2028 --> Oct 2026

In this review, we provide a comprehensive overview of the physiological roles of the MTAP-PRMT5 axis and the mechanistic principles underlying this synthetic lethality in MTAP-deficient cells. Furthermore, drawing upon insights from the analysis of real-world patient data, we discuss the clinical and molecular characteristics of MTAP-deleted tumors, review the landscape of ongoing clinical trials, and explore novel therapeutic strategies.

Although several MTA-cooperative PRMT5 synthetic lethal inhibitors have been advanced into clinical trials, only one of them (TNG908) showed brain permeability in the preclinical evaluation but failed to achieve the anticipated therapeutic exposure levels in glioblastoma in clinical trials...More importantly, compound 21 achieved significant tumor growth inhibition in an orthotopic U87MG brain tumor model, supported by its enhanced distribution and penetration within brain tissue. These results indicate the potential clinical advantages of compound 21 for treating MTAP- deleted tumors and support its potential utility against intracranial malignancies.

P1/2, N=60, Active, not recruiting, Servier Bio-Innovation LLC | N=342 --> 60 | Trial completion date: Oct 2031 --> May 2027 | Trial primary completion date: Oct 2031 --> May 2027 | Recruiting --> Active, not recruiting

MTAP-deleted thoracic tumors exhibit reproducible clinical and molecular features across populations. Our findings support the rational, globally applicable development of MTAP-targeted synthetic lethal strategies in thoracic malignancies, particularly in combination with molecular targeted agents.