Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer

Abstract

Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation.

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level

“…On the basis of the architecture of the kinase domain, ILK can be classified as a class 4 pseudokinase because of its ability to bind a nucleotide (not hydrolyzed ATP) and a cation (Mg 2+ or Mn 2+ ) [7]. This protein constitutes a signaling node inside the cell and, given its implication in multiple of physiological and pathological phenomena, it has been validated as a promising target for cancer [12,[17][18][19][20][21], as well as other diseases such as chronic kidney disease [22][23][24], inflammation [23,25] or metabolic disorders [26].…”

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level

“…On the basis of the architecture of the kinase domain, ILK can be classi ed as a class 4 pseudokinase because of its ability to bind a nucleotide (not hydrolyzed ATP) and a cation (Mg 2+ or Mn 2+ ) [7]. This protein constitutes a signaling node inside the cell and, given its implication in a myriad of physiological and pathological phenomena, it has been validated as a promising target for cance [12,[16][17][18][19][20], as well as other diseases such as chronic kidney disease [21][22][23], in ammation [22,24] or metabolic disorders [25].…”

Personalized Medicine in Oncology; a Special Issue of the Journal of Personalized Medicine

“…In ovarian cancer, Ulm and colleagues explore the potential role of integrin associated kinase as a biomarker in this malignancy [ 8 ]. Ovarian cancer tissue samples were pair-matched to normal adjacent ovarian tissue from 24 patients and tissue microarray was used to compare gene expression profiles which then led to the identification of molecular pathways for further analysis.…”