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LKB1 inactivation elicits an NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer

Wen Mi1, Xinyi Xia1, Yun Xue2

  • 1Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.

Cell Reports
|June 3, 2026
PubMed

Insights

Liver kinase B1 (LKB1) loss, independent of MTAP deletion, predicts protein arginine methyl transferase 5 (PRMT5) inhibition in lung cancer. LKB1 loss upregulates NNMT, creating a methyl sink that sensitizes cells to PRMT5 inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Protein arginine methyl transferase 5 (PRMT5) is a therapeutic target in cancers with S-methyl-5'-thioadenosine phosphorylase (MTAP) deletion.
  • 5'-methylthioadenosine (MTA) accumulation in MTAP-deleted cancers partially inhibits PRMT5 activity.
  • The role of other genetic alterations in dictating PRMT5 activity remains unclear.

Purpose of the Study:

  • To identify alternative genetic predictors of PRMT5 inhibition in cancer beyond MTAP deletion.
  • To elucidate the molecular mechanisms linking genetic alterations to PRMT5 activity.
  • To explore the therapeutic implications of targeting PRMT5 in specific cancer contexts.

Main Methods:

  • Genetic analysis to identify novel predictors of PRMT5 inhibition.
  • Mechanistic studies involving signaling pathway analysis (LKB1, SIK1/2, CRTC2).
  • Assessment of nicotinamide N-methyltransferase (NNMT) expression and its functional impact.
  • Evaluation of PRMT5 inhibitor efficacy in LKB1-deficient models.
  • In vivo studies assessing tumor growth inhibition.

Main Results:

  • Liver kinase B1 (LKB1) loss predicts PRMT5 inhibition in lung cancer, independent of MTAP deletion.
  • LKB1 loss activates SIK1/2-CRTC2 signaling, upregulating NNMT.
  • NNMT overexpression creates a "methyl sink", lowering the SAM/SAH ratio and attenuating PRMT5 activity.
  • NNMT overexpression sensitizes cells to PRMT5 inhibitors.
  • PRMT5 inhibition induces senescence in LKB1-deficient cells and synergizes with navitoclax to inhibit tumor growth.

Conclusions:

  • LKB1 deficiency represents an actionable therapeutic vulnerability in lung cancer, enabling PRMT5 inhibition.
  • LKB1 status and NNMT expression can serve as biomarkers for PRMT5-targeted therapies.
  • This study expands the potential clinical application of PRMT5 inhibitors beyond MTAP-deleted cancers.
Keywords:
CP: cancerLKB1NNMTPRMT5methyl sinksenescence

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