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Updated: Dec 25, 2025

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

Stephanie L Guerra1, Ophélia Maertens1, Ryan Kuzmickas1

  • 1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.

Cancer Cell
|April 4, 2020
PubMed

Insights

Half of KRAS-mutant non-small cell lung cancers (NSCLCs) overexpress HOXC10 due to PRC2 defects. Combined BET/MEK inhibitors target this vulnerability, offering a new therapeutic strategy for NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • KRAS mutations are prevalent in non-small cell lung cancer (NSCLC), yet effective targeted therapies remain limited.
  • Aberrant gene expression and epigenetic dysregulation contribute to NSCLC pathogenesis.

Purpose of the Study:

  • To investigate the role of HOXC10 in KRAS-mutant NSCLC.
  • To identify novel therapeutic strategies and predictive biomarkers for KRAS-mutant NSCLC.

Main Methods:

  • Analysis of HOXC10 expression in KRAS-mutant NSCLC models.
  • Treatment of xenograft and patient-derived xenograft (PDX) models with combined BET/MEK inhibitors.
  • Assessment of HOXC10 suppression, pre-replication complex (pre-RC) protein levels, and DNA damage response.

Main Results:

  • Approximately 50% of KRAS-mutant NSCLCs exhibit aberrant HOXC10 expression, linked to Polycomb Repressive Complex 2 (PRC2) defects.
  • Combined BET and MEK inhibition demonstrates efficacy in preclinical models, dependent on HOXC10 suppression.
  • HOXC10 regulates pre-RC proteins; BET/MEK inhibitors induce replication stress, DNA damage, and cell death in sensitive NSCLCs.

Conclusions:

  • Aberrant HOXC10 expression due to PRC2 defects represents a targetable vulnerability in a subset of KRAS-mutant NSCLCs.
  • Combined BET/MEK inhibition is a promising therapeutic strategy for HOXC10-expressing KRAS-mutant NSCLCs.
  • HOXC10 serves as a predictive biomarker for response to this combination therapy.
Keywords:
BETEEDHOXC10KRASMEKNSCLCPRC2SUZ12combination therapylung cancer

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