Regulation of chemosensitivity in pancreatic cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE189764 | GEO | 2022/08/22
REPOSITORIES: GEO
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Project description:Drug-tolerant “persister” cells underlie the emergence of drug-resistant clones and allow residual tumors to survive therapy; thus, represent an attractive therapeutic target to mitigate relapse. With the promising outcome, yet some resistance cases surfaced after the approval of venetoclax (ABT-199), we defined a novel invasive drug resistance mechanism induced by Bcl2 inhibitor via examining the evolution of drug tolerant persister clones generated with ABT-199 treatment. The ABT-199 drug-tolerant persister cells showed genetic alteration by losing the copy number at 18q21 paralleled with BCL2, PMAIP1 and TCF4 gene downregulation. The persister status are generated through major enhancer-remodeling mediated transcriptional activation of the super enhancer, which offered unique opportunity for overcoming the drug resistance. The insight of major determinant for ABT-199 persistence evolution identified the molecular vulnerability in Bcl2 inhibitor resistant lymphoma cells through CDK7 pathway inhibition. The combined CDK7 and BCL2 inhibition was found to be more effective against ABT-199 persistence ex vivo and in vivo rather than the parental line, and CDK7 inhibition eliminated the persister phenotype by blocking dynamic active enhancer formation to further prevent the evolution of drug resistance. Together, these studies unified genetic alteration and non-mutational adaptive response as a drug resistance mechanism, more importantly, demonstrated a rationale for transcriptional inhibition-based combination strategies to prevent and overcome drug resistance in B-cell malignancies.
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Project description:Drug-tolerant “persister” cells underlie the emergence of drug-resistant clones and allow residual tumors to survive therapy; thus, represent an attractive therapeutic target to mitigate relapse. With the promising outcome, yet some resistance cases surfaced after the approval of venetoclax (ABT-199), we defined a novel invasive drug resistance mechanism induced by Bcl2 inhibitor via examining the evolution of drug tolerant persister clones generated with ABT-199 treatment. The ABT-199 drug-tolerant persister cells showed genetic alteration by losing the copy number at 18q21 paralleled with BCL2, PMAIP1 and TCF4 gene downregulation. The persister status are generated through major enhancer-remodeling mediated transcriptional activation of the super enhancer, which offered unique opportunity for overcoming the drug resistance. The insight of major determinant for ABT-199 persistence evolution identified the molecular vulnerability in Bcl2 inhibitor resistant lymphoma cells through CDK7 pathway inhibition. The combined CDK7 and BCL2 inhibition was found to be more effective against ABT-199 persistence ex vivo and in vivo rather than the parental line, and CDK7 inhibition eliminated the persister phenotype by blocking dynamic active enhancer formation to further prevent the evolution of drug resistance. Together, these studies unified genetic alteration and non-mutational adaptive response as a drug resistance mechanism, more importantly, demonstrated a rationale for transcriptional inhibition-based combination strategies to prevent and overcome drug resistance in B-cell malignancies.
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Project description:Regulation of chemosensitivity in pancreatic cancer cells
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Project description:Acquired drug resistance prevents targeted cancer therapy from achieving stable and complete responses. Emerging evidence implicates a key role for nonmutational mechanisms including changes in cell state during early stages of acquired drug resistance. Targeting nonmutational resistance may therefore present a therapeutic opportunity to eliminate residual surviving tumor cells and impede relapse. A variety of cancer cell lines harbor quiescent, reversibly drug-tolerant âpersisterâ cells which survive cytotoxic drugs including targeted therapies and chemotherapies. These persister cells survive drug through nonmutational mechanisms which are poorly understood. Specifically targeting persister cells is a promising strategy to prevent tumor relapse. We sought to identify therapeutically exploitable vulnerabilities in persister cells using the HER2-amplified breast cancer line BT474 as an experimental model. Similar to other persister cell models, upon treatment with the HER2 inhibitor lapatinib (2uM concentration) for nine or more days, the majority of BT474 cells die, revealing a small population of quiescent surviving persister cells. Removal of lapatinib allows the persister cells to regrow and to re-acquire sensitivity to lapatinib. Subsequent lapatinib treatment re-derives persister cells. The reversibility of persister cell drug resistance indicates a nonmutational resistance mechanism. Here we provide RNAseq gene expression profiling data generated from parental BT474 cells compared to BT474 persister cells generated from nine days of treatment with 2 uM lapatinib. These data can be used to identify genes and pathways which are upregulated in persister cells, revealing potential therapeutic targets. 3 biological replicates of BT474 persister cells, two biological replicates of BT474 parental cells
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