A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers

Cancer Cell. 2020 May 11;37(5):705-719.e6. doi: 10.1016/j.ccell.2020.03.004. Epub 2020 Apr 2.

Abstract

While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.

Keywords: BET; EED; HOXC10; KRAS; MEK; NSCLC; PRC2; SUZ12; combination therapy; lung cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylonitrile / analogs & derivatives
  • Acrylonitrile / pharmacology
  • Aniline Compounds / pharmacology
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Proliferation
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation*
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Aniline Compounds
  • Biomarkers, Tumor
  • HOXC10 protein, human
  • Homeodomain Proteins
  • KRAS protein, human
  • MEK inhibitor I
  • Protein Kinase Inhibitors
  • Proteins
  • bromodomain and extra-terminal domain protein, human
  • MAP Kinase Kinase 1
  • Proto-Oncogene Proteins p21(ras)
  • Acrylonitrile