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Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Konstantinos J Mavrakis1, E Robert McDonald1, Michael R Schlabach1

  • 1Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.

Science (New York, N.Y.)
|February 26, 2016
PubMed

Insights

MTAP-deleted cancers accumulate MTA, inhibiting PRMT5. This creates a vulnerability to PRMT5 inhibition, suggesting PRMT5 inhibitors as a potential therapy for these tumors.

Area of Science:

  • Oncology
  • Biochemistry
  • Cancer Genetics

Background:

  • 5-Methylthioadenosine phosphorylase (MTAP) is crucial in the methionine salvage pathway.
  • MTAP gene deletions are common in human cancers due to proximity to the CDKN2A tumor suppressor gene.

Purpose of the Study:

  • To investigate the functional consequences of MTAP deletion in cancer.
  • To identify therapeutic strategies targeting MTAP-deficient cancers.

Main Methods:

  • Large-scale short hairpin RNA (shRNA) screen across 390 cancer cell line models.
  • Analysis of metabolite accumulation (methylthioadenosine - MTA) in MTAP-deleted cells.
  • Assessment of PRMT5 methyltransferase activity and cellular viability.

Main Results:

  • MTAP-deficient cancer cells exhibit impaired viability upon PRMT5 depletion.
  • Accumulated MTA in MTAP-deleted cells inhibits PRMT5 methyltransferase activity.
  • MTAP deletion sensitizes cells to PRMT5 inhibition; MTAP reintroduction rescues this dependence.

Conclusions:

  • MTA accumulation in MTAP-deleted cancers leads to a hypomorphic PRMT5 state, creating sensitivity to PRMT5 inhibition.
  • PRMT5 inhibitors represent a promising therapeutic avenue for MTAP/CDKN2A-deleted tumors.

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