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Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform

Riccardo Bevilacqua1, Paola Gasperini1, Thomas Cantore1

  • 1Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.

NPJ Precision Oncology
|April 18, 2026
PubMed

Insights

Loss of the 9p21 locus, common in cancers, creates vulnerabilities. Researchers found specific drugs like cytarabine and gemcitabine are more effective in 9p21-deficient bladder cancer cells, offering new precision medicine options.

Area of Science:

  • Genomics and Cancer Biology
  • Precision Medicine
  • Drug Discovery

Background:

  • Homozygous loss of the 9p21 locus, including CDKN2A, CDKN2B, and MTAP genes, is a frequent event in various cancers.
  • This genetic alteration presents a potential target for developing novel precision medicine strategies.

Purpose of the Study:

  • To identify drug vulnerabilities associated with the 9p21 locus loss.
  • To explore the efficacy of specific drug combinations targeting MTAP synthetic lethal partners.

Main Methods:

  • Generated isogenic bladder cancer cell models with 9p21 locus loss.
  • Conducted a large-scale drug screen of 2,349 compounds.
  • Investigated drug combinations targeting MTAP synthetic lethal partners (PRMT5, MAT2A) and ATR/CHK1 pathway inhibitors.

Main Results:

  • Cytarabine and methotrexate showed significantly higher efficacy in 9p21-compromised bladder cancer cells.
  • Nucleoside analogs, including gemcitabine, demonstrated genotype-specific activity.
  • Synergistic effects were observed with combinations of cytarabine and MTAP inhibitor drugs (MRTX1719, AG-270), alongside ATR/CHK1 inhibitors.

Conclusions:

  • The 9p21 locus loss confers sensitivity to specific nucleoside analogs and presents exploitable vulnerabilities.
  • Targeting MTAP synthetic lethality and DNA damage/replication stress pathways offers a promising therapeutic strategy for 9p21-loss cancers.
  • Validated findings in pancreatic cancer, mesothelioma models, and bladder cancer patient-derived organoids highlight strong translational potential.

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