Effect of CDK8/19 kinase inhibitor SNX 631 on OV90 parental and anoikis resistant isogenic lines

Anoikis resistance or evasion of cell death triggered by matrix detachment is a hallmark of cancer cell survival and metastasis. We show that repeated exposure to suspension stress followed by recovery under attached conditions leads to development of anoikis resistance. The acquisition of anoikis resistance is associated with enhanced invasion, chemoresistance, and immune evasion in vitro and distant metastasis in vivo. This acquired anoikis resistance is not genetic, persisting for a finite duration without detachment stress, but is sensitive to CDK8/19 Mediator kinase inhibition that can also reverse anoikis resistance. Transcriptomic analysis reveals that CDK8/19 kinase inhibition induces bidirectional transcriptional regulation in both sensitive and resistant cells disrupting the balanced reprogramming required for anoikis adaptation and resistance and reversing some resistance associated pathways while enhancing others. Both anoikis resistance and in vivo metastatic growth of ovarian cancers are sensitive to CDK8/19 inhibition, thereby providing a therapeutic opportunity to both prevent and suppress ovarian cancer metastasis Overall design: Transcriptomic profiling of the effect of CDK8/19 inhibition using SNX631 on OV90 parental ( anoikis sensitive) and adapted isogenic OV90 resistant lines in attached or suspension cultures with either pretreatment in 2D culture alone or co- treatment with suspension culture in adapted resistant lines.