MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies

Area of Science:

• Oncology
• Genetics
• Biochemistry

Background:

• Homozygous deletion of the 9p21.3 locus, including CDKN2A/B and methylthioadenosine phosphorylase (MTAP) genes, affects 15% of human cancers.
• While CDKN2A is a known tumor suppressor, MTAP's role in tumorigenesis is context-dependent, impacting the methionine salvage pathway.
• Loss of MTAP creates synthetic vulnerabilities, yet targeted therapies have shown limited clinical success.

Purpose of the Study:

• To provide an updated perspective on MTAP loss incidence across various cancer types.
• To elucidate the impact of MTAP loss on tumor metabolism, immune microenvironment, and progression.
• To summarize preclinical and clinical therapeutic strategies targeting MTAP-null tumors.

Main Methods:

• Systematic literature review and analysis of existing data on MTAP loss in cancer.
• Evaluation of preclinical studies investigating therapeutic strategies for MTAP-deficient tumors.
• Assessment of the current landscape of clinical trials for MTAP-targeted inhibitors.

Main Results:

• Consolidated incidence data of MTAP loss in diverse cancers.
• Elucidation of MTAP loss effects on tumor metabolism and immune interactions.
• Summary of preclinical findings and clinical trial outcomes for MTAP-targeted therapies.

Conclusions:

• MTAP loss presents a significant therapeutic target with complex downstream effects.
• Current MTAP-targeted therapies face limitations, necessitating improved strategies.
• Future research should explore rational combination therapies, potentially beyond the PRMT5/MAT2A axis, to effectively treat MTAP-null cancers.