Breaking Boundaries in Cancer Therapy: Harnessing Chromothripsis- Induced Mutations for Targeted BCL2 Protein Destabilization.

Abstract

Chromothripsis, a phenomenon of massive genomic rearrangements, introduces extensive mutations in critical genes, affecting cell survival and apoptosis. Among these genes, the BCL2 (B-cell lymphoma 2) gene, which plays a crucial antiapoptotic role in cancer cells, is often subjected to significant alterations. Here, we present a computational pipeline to model and analyze the structural and functional impacts of chromothripsis-induced Single-Nucleotide Polymorphisms (SNPs) within the BCL2 gene. This pipeline integrates mutation simulation, homology modeling, and protein inter-action analysis to evaluate the stability and apoptotic potential of BCL2 mutations. These results indicate that chromothripsis-induced mutations can destabilize the Bcl-2 protein, thereby disrupting its binding affinity with apoptotic regulators, such as Bax. These findings support the potential of ergodic anticancer therapy to exploit such mutations, facilitating the apoptosis of cancer cells. Our computational model offers a novel in silico approach for understanding mutation-driven alterations in cancer biology, aiding the development of therapeutic strategies targeting apoptotic pathways.