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A coding single-nucleotide polymorphism in lysine demethylase KDM4A associates with increased sensitivity to mTOR

Capucine Van Rechem1, Joshua C Black1, Patricia Greninger1

  • 1Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|January 8, 2015
PubMed
Abstract

Insights

A specific gene variant (SNP-A482) in KDM4A is linked to worse non-small cell lung cancer outcomes and increased sensitivity to mTOR inhibitors, suggesting its potential as a biomarker.

Area of Science:

  • Genetics
  • Cancer Biology
  • Pharmacology

Background:

  • Single nucleotide polymorphisms (SNPs) in chromatin-modulating factors are understudied regarding their impact on cancer.
  • Understanding the role of coding SNPs in cancer progression and treatment response is crucial for targeted therapies.

Purpose of the Study:

  • To investigate the functional impact of a coding SNP (SNP-A482) in the KDM4A gene.
  • To determine the association of SNP-A482 with non-small cell lung cancer (NSCLC) patient outcomes and therapeutic response.

Main Methods:

  • Analysis of allelic frequencies of SNP-A482 across ethnic populations.
  • Assessment of SNP-A482's effect on KDM4A protein turnover.
  • Drug screening of 87 compounds against cells with different SNP-A482 genotypes.
  • Evaluation of mTOR inhibitor sensitivity in relation to SNP-A482 status.

Main Results:

  • SNP-A482 exhibits varying allelic frequencies globally and correlates with differential outcomes in NSCLC patients.
  • The SNP-A482 variant influences KDM4A protein turnover.
  • Cells with homozygous SNP-A482 show heightened sensitivity to mTOR inhibitors.
  • mTOR inhibitors decrease SNP-A482 protein levels, mirroring effects of KDM4A depletion.

Conclusions:

  • The first identified coding SNP in a lysine demethylase (KDM4A) is associated with poorer NSCLC prognosis.
  • This SNP alters protein turnover and predicts enhanced sensitivity to mTOR inhibitors, positioning it as a potential biomarker.
  • SNP-A482 represents a therapeutic target for combination strategies in NSCLC treatment.

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