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Aneuploidy sensitizes cells to SREBP-pathway inhibition in squamous cell carcinoma

Nadja Zhakula-Kostadinova1,2, Sejal Jain3, Zeinab Amini-Farsani2

  • 1Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons.

Biorxiv : the Preprint Server for Biology
|May 18, 2026
PubMed

Insights

Chromosome 3q-gain in squamous cell carcinomas (SCCs) creates a vulnerability in the mevalonate pathway. Targeting sterol regulatory element-binding protein (SREBP) signaling offers a new therapeutic strategy for SCCs.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Squamous cell carcinomas (SCCs) frequently exhibit chromosome-arm aneuploidies, notably 3q-gain.
  • The functional impact of these aneuploidies on cancer development and therapeutic vulnerabilities is not well understood.

Purpose of the Study:

  • To identify therapeutic targets driven by aneuploidy in SCCs.
  • To investigate the role of chromosome 3q-gain in cellular dependencies and drug sensitivities.

Main Methods:

  • Genome-wide CRISPR interference (CRISPRi) screens were conducted in isogenic lung epithelial cells with or without 3q-gain.
  • Drug-repurposing screens were performed to identify compounds targeting 3q-gain-specific vulnerabilities.
  • Transcriptomic and lipidomic profiling were used to analyze molecular alterations.

Main Results:

  • Both screens identified a dependency on the mevalonate pathway specifically in 3q-gain cells.
  • 3q-gain cells showed heightened sensitivity to sterol regulatory element-binding protein (SREBP) disruption.
  • Inhibition of SREBP signaling impaired SCC cell viability and suppressed tumor growth in vivo.

Conclusions:

  • Chromosome 3q-gain confers a specific vulnerability to SREBP-pathway inhibition in SCCs.
  • This identifies an aneuploidy-driven, targetable liability for lipid-targeted precision therapies in squamous tumors.

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