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Breaking Boundaries in Cancer Therapy: Harnessing Chromothripsisinduced Mutations for Targeted Bcl-2 Protein

Sergey Shityakov1, Michael Nosonovsky1,2, Ekaterina V Skorb1

  • 1Infochemistry Scientific Center (ISC), ITMO University, 9 Lomonosova, St. Petersburg, 191002, Russia.

Current Drug Discovery Technologies
|June 3, 2025
PubMed

Insights

Chromothripsis causes mutations in the BCL-2 gene, impacting cancer cell survival. Our computational model shows these mutations destabilize BCL-2, offering new therapeutic targets for cancer apoptosis.

Area of Science:

  • Genomics
  • Cancer Biology
  • Computational Biology

Background:

  • Chromothripsis involves massive genomic rearrangements leading to mutations in critical genes.
  • The BCL-2 gene is vital for anti-apoptotic functions in cancer cells and is frequently altered by chromothripsis.

Purpose of the Study:

  • To develop and utilize a computational pipeline for analyzing the structural and functional effects of chromothripsis-induced Single-Nucleotide Polymorphisms (SNPs) in the BCL-2 gene.
  • To assess the impact of these mutations on BCL-2 protein stability and its interaction with apoptotic regulators.

Main Methods:

  • Integrated mutation simulation, homology modeling, and protein interaction analysis.
  • Evaluated BCL-2 protein stability and apoptotic potential using an in silico approach.

Main Results:

  • Chromothripsis-induced mutations were found to destabilize the BCL-2 protein.
  • These mutations disrupt the binding affinity between BCL-2 and apoptotic regulators like Bax.

Conclusions:

  • The study highlights how chromothripsis-induced mutations can impair BCL-2's anti-apoptotic function.
  • Findings support ergodic anticancer therapies targeting these mutations to induce cancer cell apoptosis and inform new therapeutic strategies.
Keywords:
BCL-2Chromothripsisapoptosiscancer therapy.ergodic therapymutation impactprotein modeling

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