{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["12(3)"],"submitter":["Huang S"],"pubmed_abstract":["Therapeutic resistance is the major challenge in clinic for patients with mantle cell lymphoma (MCL), an aggressive subtype of B-cell lymphoma. In addition to the FDA-approved Bruton's tyrosine kinase (BTK) inhibitors, multiple clinical trials have demonstrated clinical benefits in targeting BCL-2 by venetoclax and reported to greatly improve clinical outcome for refractory/relapsed patients with MCL alone or in combination with BTK inhibitors. However, resistance to venetoclax is no exception and marks as a new clinic challenge. To decode the underlying mechanisms driving venetoclax resistance, we established two MCL cell lines, Mino-Re and Rec1-Re, with acquired resistance to venetoclax from sensitive Mino and Rec-1. Using reverse phase protein assay (RPPA), an agnostic proteomic approach, we identified targetable signaling pathways that are associated with acquired venetoclax resistance in Mino-Re and Rec1-Re cells. A panel of pro-survival signals was identified to correlate well with venetoclax-resistance, including increased expression of MCL-1, BCL-xL and AKT phosphorylation, and decreased expression of BIM, BAX and PTEN. Based on a high throughput drug screening of over 320 FDA-approved/investigational drugs in the paired venetoclax-sensitive and -resistant cell lines Mino-Re and Rec1-Re, we identified the top candidates that are capable to overcome acquired venetoclax resistance in these cells. The best candidate is PIK-75, a dual inhibitor targeting both PI3K and CDK9. Its action to overcome venetoclax resistance was further confirmed in additional cell lines with primary venetoclax resistance (n=4) and primary patient samples (n=21). Mechanistically, PIK75 treatment potently diminished the elevated MCL-1 expression and AKT activation in cells with acquired or primary venetoclax resistance and resulted in potent anti-MCL activity to overcome these resistances. In addition, PIK75 is also potent in overcoming tumor microenvironment (TME)-associated venetoclax resistance. Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance."],"journal":["American journal of cancer research"],"pagination":["1102-1115"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8984906"],"repository":["biostudies-literature"],"pubmed_title":["PIK-75 overcomes venetoclax resistance <i>via</i> blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma."],"pmcid":["PMC8984906"],"pubmed_authors":["Wang M","Liu Y","Huang S","Chen Z","Jiang VC"],"additional_accession":[]},"is_claimable":false,"name":"PIK-75 overcomes venetoclax resistance <i>via</i> blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.","description":"Therapeutic resistance is the major challenge in clinic for patients with mantle cell lymphoma (MCL), an aggressive subtype of B-cell lymphoma. In addition to the FDA-approved Bruton's tyrosine kinase (BTK) inhibitors, multiple clinical trials have demonstrated clinical benefits in targeting BCL-2 by venetoclax and reported to greatly improve clinical outcome for refractory/relapsed patients with MCL alone or in combination with BTK inhibitors. However, resistance to venetoclax is no exception and marks as a new clinic challenge. To decode the underlying mechanisms driving venetoclax resistance, we established two MCL cell lines, Mino-Re and Rec1-Re, with acquired resistance to venetoclax from sensitive Mino and Rec-1. Using reverse phase protein assay (RPPA), an agnostic proteomic approach, we identified targetable signaling pathways that are associated with acquired venetoclax resistance in Mino-Re and Rec1-Re cells. A panel of pro-survival signals was identified to correlate well with venetoclax-resistance, including increased expression of MCL-1, BCL-xL and AKT phosphorylation, and decreased expression of BIM, BAX and PTEN. Based on a high throughput drug screening of over 320 FDA-approved/investigational drugs in the paired venetoclax-sensitive and -resistant cell lines Mino-Re and Rec1-Re, we identified the top candidates that are capable to overcome acquired venetoclax resistance in these cells. The best candidate is PIK-75, a dual inhibitor targeting both PI3K and CDK9. Its action to overcome venetoclax resistance was further confirmed in additional cell lines with primary venetoclax resistance (n=4) and primary patient samples (n=21). Mechanistically, PIK75 treatment potently diminished the elevated MCL-1 expression and AKT activation in cells with acquired or primary venetoclax resistance and resulted in potent anti-MCL activity to overcome these resistances. In addition, PIK75 is also potent in overcoming tumor microenvironment (TME)-associated venetoclax resistance. Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022","modification":"2025-04-05T13:24:17.721Z","creation":"2025-04-05T13:24:17.721Z"},"accession":"S-EPMC8984906","cross_references":{"pubmed":["35411248"]}}