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Published on: May 27, 2021

MTAP Deficiency as a Metabolic Vulnerability in Cancer: Implications for Synthetic Lethal Therapy

Hiroaki Ikushima1, Hidenori Kage1

  • 1Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Cancer Science
|May 27, 2026
PubMed

Insights

The common 9p21.3 deletion in cancer, involving methylthioadenosine phosphorylase (MTAP) loss, creates a vulnerability. Targeting protein arginine methyltransferase 5 (PRMT5) exploits this, offering a novel synthetic lethality strategy for MTAP-deleted tumors.

Area of Science:

  • Oncology
  • Genomics
  • Metabolic pathways

Background:

  • The 9p21.3 locus deletion, encompassing CDKN2A/B and MTAP genes, is frequent in cancers.
  • MTAP loss, previously overlooked, reveals significant metabolic vulnerabilities in cancer cells.
  • MTAP deficiency leads to increased reliance on PRMT5, presenting a therapeutic target.

Purpose of the Study:

  • To review the MTAP-PRMT5 axis's physiological roles and synthetic lethality mechanisms in MTAP-deficient cancers.
  • To analyze clinical and molecular features of MTAP-deleted tumors using real-world patient data.
  • To explore current clinical trials and novel therapeutic strategies targeting this vulnerability.

Main Methods:

  • Literature review of MTAP-PRMT5 axis.
  • Analysis of real-world patient data for MTAP-deleted tumors.
  • Review of ongoing clinical trials and emerging therapeutic strategies.

Main Results:

  • MTAP loss confers dependency on PRMT5, enabling synthetic lethality.
  • PRMT5 inhibition demonstrates efficacy in MTAP-deleted tumor models.
  • Distinct clinical and molecular profiles characterize MTAP-deleted tumors.

Conclusions:

  • The MTAP-PRMT5 axis represents a promising therapeutic vulnerability in oncology.
  • Targeting PRMT5 offers a selective treatment strategy for MTAP-deleted cancers.
  • Further clinical investigation is warranted to translate these findings into patient benefit.
Keywords:
MAT2AMTAPPRMT5metabolic vulnerabilitysynthetic lethality

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