Biology subjects

Gahramanov, V.

Publications and source records attributed to Gahramanov, V..

5 recordsLinked to original sources

bioRxiv2026

Systematic Generation of Mutations at Topoisomerase II Cleavage Sites Enables Cancer Adaptation to Doxorubicin Therapy

Acquired resistance to chemotherapy remains a major cause of treatment failure. Here, we investigate the early events underlying the development of resistance to doxorubicin (Dox), one of the most widely used anticancer agents, during repeated drug exposure. Dox intercalates into DNA at sites influenced by chromatin structure and inhibits the DNA religation step of topoisomerase II (Top2), thereby inducing double-strand DNA breaks (DSBs). Here, we show that, in the subpopulation of cancer cells that survive initial Dox treatment, repair of Dox-induced DSBs leads to the accumulation of recurrent mutations at Top2 cleavage sites. These mutations prevent the formation of Dox-induced DSBs at the same loci upon subsequent exposures, effectively protecting the genome from Top2-mediated DNA damage and promoting the development of drug resistance. Importantly, the loss of Top2-dependent DNA cleavage and relaxation caused by these mutations increases the reliance of adapted cells on topoisomerase I (Top1), thereby sensitizing them to Top1 inhibitors. Together, our findings reveal a previously unrecognized mechanism of resistance based on the active generation of highly adaptive mutations, providing new insight into cancer evolution under therapeutic pressure.

cancer biology↗

bioRxiv2026

Mega-frequency mutagenesis: generation of non-random precise mutations with extremely high frequency upon adaptation of cancer cells to drugs and stress

Acquiring drug resistance is a major problem in cancer treatment. As cancers adapt to chemotherapy, chromatin landscape becomes altered in subpopulations of persister cells to acquire gene expression patterns that provide drug resistance. The increased level of stress-induced random mutagenesis in cancer has also been linked to acquisition of drug resistance. Here we show that during adaptation to conventional cytotoxic chemotherapies or targeted therapies, tens of thousands of mutations are generated, and the probability of acquisition of these mutations at specific positions can reach 50% and even higher. A large fraction of these mutations is highly recurrent and non-random. The patterns of the recurrent mutations are specific to the drug target and are unrelated to the chemical nature of the drug. Surprisingly, these mutations are progressively generated at the non-dividing pseudo-senescence stage following drug exposure, and at this stage, selection is not involved in their accumulation. Notably, these mutations are highly enriched within or near binding motifs of certain transcription factors, like KLF9, IRF1 and others. Therefore, a mechanism for precise generation of mutations at specific positions with extremely high rates appears to be triggered upon drug adaptation, and these precise mutations may affect activities of a set of transcription factors.

cancer biology↗

bioRxiv2026

Epigenetic Liquid Biopsy Enables Universal Mutation-Agnostic Molecular Surveillance for High-Risk Neuroblastoma

Pediatric solid tumors present a challenge for precision oncology as most tumors harbor low mutational burden, limiting the applicability of standard mutation-based liquid biopsy approaches for molecular monitoring. To overcome this, we developed a mutation-independent liquid biopsy framework based on Oxford Nanopore Technology sequencing, utilizing robust DNA methylation-based biomarkers for detection and surveillance of high-risk neuroblastoma (HR-NBL), a common pediatric solid tumor. Comparative analysis of tumor-derived DNA methylation profiles against a comprehensive atlas of normal human cell types identified 72 NBL-specific differentially methylated regions (termed meNBLs). Integration of 25 selected meNBLs into the methylation atlas enabled quantitative deconvolution of NBL-derived cfDNA, outperforming copy number and mutation-based estimates. NBL-specific blood plasma-derived cfDNA was detected at diagnosis but not in healthy controls, absent during remission, and markedly elevated at relapse, even before clinical detection of disease recurrence. These findings establish methylation-based deconvolution as a robust, mutation-independent approach for cfDNA monitoring in HR-NBL.

cancer biology↗

bioRxiv2023

Cancer Cell`s Seven Achilles Heels: Consideration for desing of anti-cancer drug combinations.

Loss of function screens using shRNA and CRISPR are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA and CMAP analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent "weak points" or "Achilles heels", whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These "weak points" include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the "weak points" pathways. Our findings described here imply that inhibitors of the "weak points" pathways should be considered as primary candidates in a search for synergistic drug combinations.

cancer biology↗

bioRxiv2021

Homologous recombination repair creates mutations in the non-coding genome that alter Topoisomerase-1 cleavage sites & orchestrates irinotecan resistance

Resistance to chemotherapy is a leading cause of treatment failure. Drug-resistance mechanisms involve mutations in specific proteins or changes in their expression levels. It is commonly understood that resistance mutations happen randomly prior to treatment and are selected during the treatment. However, selection of drug-resistant mutants in culture could be achieved by multiple drug exposures of cloned genetically identical cells, and thus cannot result from selection of pre-existent mutations. Accordingly, adaptation must involve generation of mutations de-novo upon drug treatment. Here we explored the origin of resistance mutations to a widely used Top1 inhibitor irinotecan, which triggers DNA breaks, causing cytotoxicity. Resistance mechanism involved gradual accumulation of recurrent mutations in non-coding regions of DNA at Top1-cleavage sites. Surprisingly, cancer cells had higher number of such sites than reference genome, which may define their increased sensitivity to irinotecan. Homologous recombination repair of DNA double strand breaks at these sites following initial drug exposures gradually reverted cleavage-sensitive "cancer" sequences back to cleavage-resistant "normal" sequences. These mutations reduced generation of DNA breaks upon subsequent exposures, thus gradually increasing the drug resistance. Together, large target size for mutations and their Top1-guided generation lead to their gradual and rapid accumulation, synergistically accelerating development of resistance. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/470089v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@d9d93forg.highwire.dtl.DTLVardef@45b88forg.highwire.dtl.DTLVardef@157cafeorg.highwire.dtl.DTLVardef@cff4a4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗