Abstract B49: The role of LATS kinases in regulation of CDK4/6 in ovarian cancer
Authors: Saini Siddharth , Sesay Fatmata , Litovchick Larisa 
Published: August 2018

High-grade ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer with little improvement in survival over the last decade. Identification of the “druggable” cancer-driving pathways could facilitate the development of effective treatments for HGSOC patients. Oncogenomic analyses of HGSOC tumors revealed widespread genome alterations but only a few recurrent mutations that could be targeted by either approved or experimental therapeutics. We observed copy number losses of genes encoding LATS1 and LATS2 tumor suppressor protein kinases in approximately 60% of HGSOC tumors analyzed by TCGA study. Loss of LATS kinases could contribute to cancer pathogenesis because of their important role in the Hippo tumor suppressor pathway that is known to control cell invasion, migration, and proliferation though inhibition of the oncogenic transcription factors YAP and TAZ. Here, we describe an alternative mechanism by which LATS kinases can control cell proliferation and discuss the implications of this finding for HGSOC treatment. In previous studies, LATS2 kinase was shown to promote growth suppressor function of retinoblastoma family. LATS2 phosphorylation of DYRK1A protein kinase promoted assembly of the transcriptional repressor DREAM. DREAM assembles during G0/G1 when RB-like p130 binds E2F4, DP1 and a stable complex of five proteins, including RBBP4, LIN9, LIN37, LIN52, and LIN54 (MuvB core), and inhibits the expression of more than 800 cell cycle-regulated genes. Here, we report that LATS1 and LATS2 function redundantly in the regulation of DREAM in SKOV3 ovarian cancer cells and in the nontransformed fallopian tube epithelial (FTE) cells. Downregulation of LATS1 and LATS2 expression resulted in increased proliferation and promoted transformed phenotype of these cells, suggesting that loss of these genes could contribute to ovarian cancer aggressiveness. Interestingly, we observed that depletion of both LATS kinases in these cells resulted in markedly increased phosphorylation of the retinoblastoma family proteins pRB and p130. This phosphorylation was likely mediated by CDK4/6 kinases because it was completely abolished by treatment of cells with the highly selective CDK4/6 inhibitor, PD-0332991 (palbociclib). We investigated the mechanism of CDK4/6 activation, and found that downregulation of LATS kinases in SKOV3 or FTE cells resulted in a markedly increased expression of cyclin D1 at the protein, but not at the mRNA level. In a recent study, loss of the CDK4/6 inhibitor, p16, correlated with increased sensitivity of ovarian cancer cell lines to palbociclib. Therefore, we tested whether aberrant activation of CDK4/6 in LATS1/2-depleted cells could similarly predispose ovarian cancer cells to palbociclib growth inhibition. Indeed, downregulation of LATS kinases in SKOV3 cells resulted in 3-fold decrease of palbociclib IC50 compared to control cell lines. Importantly, clinical trials using palbociclib and analogous drugs in several types of cancer revealed a wide range of outcomes, emphasizing significance of research that will help to predict tumor sensitivity. Currently, there are no HGSOC-specific clinical trials using palbociclib. Our findings reported here support the concept that frequent genetic losses of LATS1 and LATS2 kinases in HGSOC could provide a rationale for using CDK4/6 inhibitors, such as palbociclib, for treatment of patients suffering from this disease.

Citation Format: Siddharth Saini, Fatmata Sesay, Larisa Litovchick. The role of LATS kinases in regulation of CDK4/6 in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B49.