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MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis

Katya Marjon1, Michael J Cameron1, Phong Quang1

  • 1Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.

Cell Reports
|April 13, 2016
PubMed

Insights

Cancer cells with MTAP deletion are vulnerable to targeting PRMT5 and MAT2A. Loss of methylthioadenosine phosphorylase (MTAP) leads to accumulation of MTA, inhibiting PRMT5, creating a synthetic lethal interaction.

Area of Science:

  • Oncology
  • Biochemistry
  • Cancer Metabolism

Background:

  • Homozygous deletions of the CDKN2A gene, including the adjacent methylthioadenosine phosphorylase (MTAP) gene, are common in various cancers.
  • Loss of MTAP leads to the accumulation of its substrate, methylthioadenosine (MTA).

Purpose of the Study:

  • To identify therapeutic vulnerabilities in cancer cells with MTAP deletions.
  • To elucidate the mechanistic basis for synthetic lethality in MTAP-deleted cancers.

Main Methods:

  • shRNA screening to identify vulnerable enzymes in MTAP-deleted cells.
  • Metabolomic and biochemical analyses to understand enzyme interactions.
  • Enzyme inhibition profiling.

Main Results:

  • Methionine adenosyltransferase II alpha (MAT2A) and PRMT5 were identified as vulnerable targets in MTAP-deleted cells.
  • Accumulated MTA in MTAP-deleted cells acts as a potent inhibitor of PRMT5.
  • Depletion of MAT2A or PRMT5 selectively impairs growth and reduces PRMT5 methylation activity in MTAP-deleted cells.
  • This vulnerability extends to PRMT5 co-complex proteins like RIOK1.

Conclusions:

  • MTAP deletion creates a dependency on PRMT5 activity, making MTAP-deleted cancers susceptible to PRMT5 or MAT2A inhibition.
  • The PRMT5 methylation axis represents a promising therapeutic target for CDKN2A/MTAP-deleted cancers.

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