Abstract A019: Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition

Abstract

Abstract Anoikis resistance or evasion of cell death triggered by cell detachment is a hallmark of cancer that is concurrent with cell survival and metastasis. Phenotypes of intrinsically anoikis resistant cancer cells have been extensively investigated but the mechanism of how exposure to suspension stress may lead to the acquisition of an anoikis resistance phenotype has not been previously described. Here we show that cycles of suspension stress followed by attached growth, mimicking an in vivo scenario, lead to adaptation to anoikis and acquisition of resistance to cell death, concomitant with increased chemoresistance and metastasis in vivo. Based on mutational and clonal population behavior analysis and modeling using a modified Luria-Delbrück’s fluctuation analysis we find that such acquired anoikis resistance is not genetic. Transcriptional reprogramming is, however,essential for the acquisition of adaptive anoikis resistance in vitro and in vivo, since these processes are exquisitely sensitive to selective inhibition of the CDK8/19 Mediator kinase, a broad-spectrum regulator of transcriptional reprogramming. Longitudinal analysis of the acquisition of anoikis resistance indicates strong repression programs along with a hybrid epithelial/mesenchymal phenotype and an enhanced need for oxidative phosphorylation, resulting in the emergence of anoikis-adapted cells that also efficiently evade T cell-mediated immune surveillance. Our data demonstrate that recovery from the brink of anoikis is a direct contributor to metastasis in ovarian cancer and can be therapeutically prevented using inhibitors of CDK8/19 Mediator kinase Citation Format: Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Macias Quintero, Lara Ianov, sarthak Sahoo, Mohit Kumar Jolly, Elizabeth Worthey, Nadine Hempel, Abhyudai Singh, Eugenia Broude, Karthikeyan Mythreye. Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A019.