Loss of compensatory pro-survival and anti-apoptotic modulator, IKKε, sensitizes ovarian cancer cells to CHEK1 loss through an increased level of p21

// Marianne K. Kim 1 , Dong J. Min 2 , George Wright 3 , Ian Goldlust 4 , Christina M. Annunziata 1 1 Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 2 Transgenic Oncogenic and Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 3 Biometrics Research Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 4 NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD 20892 Correspondence to: Christina M. Annunziata, e-mail: annunzic@mail.nih.gov Keywords: shRNAs, therapeutic targets, IKKe, CHEK1, p21, ovarian cancer Received: October 02, 2014      Accepted: October 27, 2014      Published: November 15, 2014 ABSTRACT Ovarian cancer (OC) is extremely heterogeneous, implying that therapeutic strategies should be specifically designed based on molecular characteristics of an individual’s tumor. Previously, we showed that IKKe promotes invasion and metastasis in a subset of OCs. Here, we identified CHEK1 as an IKKe-dependent lethal gene from shRNA kinome library screen. In subsequent pharmacological intervention studies, the co-inhibition of IKKe and CHEK1 was more effective in killing OC cells than single treatment. At the molecular level, co-inhibition dramatically decreased pro-survival proteins, but increased proteins involved in DNA damage and apoptosis. IKKe-knockdown increased p21 levels, while overexpression of wild-type IKKe, but not a kinase dead IKKe mutant decreased p21 levels. We further demonstrated that the depletion of p21 rendered OC cells more resistant to cell death induced by co-inhibition of IKKe and CHEK1. In conclusion, we revealed a novel interplay between IKKe, CHEK1 and p21 signaling in survival of OC. Our study provides a rationale for the clinical development of specific IKKe inhibitor and for usage of IKKe as an exploratory marker for resistance to CHEK1 inhibitors in the clinic. The interplay provides one potential explanation as to why very few clinical responses were achieved in patients treated with single-agent CHEK1 inhibitors.