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MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer

Fadi E Pulous1, Barbara Steurer1, Frank W Pun2

  • 1Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA.

Drug Discovery Today
|September 21, 2024
PubMed

Insights

Targeting MAT2A (MET adenosyl transferase 2 alpha) offers a novel anti-tumor therapy. Its inhibition exploits cancer vulnerabilities, particularly in MTAP-deficient tumors, by disrupting metabolic and transcriptional processes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Carcinogenesis involves metabolic and transcriptional reprogramming, creating vulnerabilities for targeted therapies.
  • MET adenosyl transferase 2 alpha (MAT2A) regulates cellular methionine metabolism and epigenetic transcription.
  • Aberrant MAT2A function drives malignant transformation via metabolic addiction, transcriptional rewiring, and immune modulation.

Purpose of the Study:

  • To review the biological roles of MAT2A in cancer.
  • To outline the current landscape of MAT2A inhibitors.
  • To highlight clinical developments and opportunities for MAT2A-targeted therapies.

Main Methods:

  • Literature review of MAT2A biology and its role in cancer.
  • Analysis of current MAT2A inhibitor drug development.
  • Summary of recent clinical trial data and therapeutic strategies.

Main Results:

  • MAT2A plays a critical role in sustaining MTAP-deficient tumors, presenting a synthetic lethality vulnerability.
  • MAT2A inhibition impacts tumor metabolism, gene expression, and the tumor microenvironment (TME).
  • Several MAT2A inhibitors are in preclinical and clinical development.

Conclusions:

  • Pharmacological inhibition of MAT2A is a promising therapeutic strategy against various cancers, especially those with MTAP loss.
  • Targeting MAT2A offers a novel approach to combat tumor growth by exploiting metabolic and epigenetic vulnerabilities.
Keywords:
MAT2A and MTAP synthetic lethalityMAT2A-driven tumor progressionMTAP-null cancerscancer cell metabolismmethionine synthesis

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