Cancer Cell Resistance to Aurora Kinase Inhibitors: Identification of Novel Targets for Cancer Therapy

Abstract

Drug resistance is the major obstacle to successful cancer therapy. Our study focuses on resistance to Aurora kinase inhibitors tested as anti-cancer drugs in clinical trials. We have used 2D electrophoresis in the pH ranges of 4-7 and 6-11 followed by protein identification using MALDI-TOF/TOF to compare the protein composition of HCT116 colon cancer cells either sensitive to CYC116 and ZM447439 inhibitors or resistant toward these drugs. The analysis also included p53(+/+) and p53(-/-) phenotypes of HCT116 cells. Our findings demonstrate that platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439 only where resistance is related to p53. On the other hand, serine hydroxymethyltransferase was found to promote the tumor growth in cells resistant to CYC116 without the influence of p53. Computer modeling of interaction networks highlighted a direct link of the p53-independent mechanism of resistance to CYC116 with autophagy. Importantly, serine hydroxymethyltransferase, serpin B5, and calretinin represent the target proteins that may help overcome resistance in combination therapies. In addition, serpin B5 and calretinin appear to be candidate biomarkers that may be accessible in patients for monitoring of cancer therapy with ease.

Aurora kinases: novel therapy targets in cancers

“…Given overexpression or gene amplification of Aurora kinases has been identified in diverse cancers, making them become potent targets of cancer therapy, a series of AKIs have been produced for the past decades and inhibition of expression or activity of Aurora kinases by AKIs indeed suppresses cell proliferation, migration and invasion in cancer cells [29, 119, 120], inhibits the progress and growth of many cancers [95, 121, 122] as Figure 5 shown, and more exciting is that some AKIs have already been used into clinical trials [123–136] (Table 1). Based on current researches and observations, MLN8237 (Alisertib), one of AURKA selective inhibitor, and the AURKB selective inhibitor AZD1152 are successfully attracted researchers attention and are undergoing III clinical trials due to their potential dominant suppression for cancer treatment [125, 127].…”

Aurora Kinases as Druggable Targets in Pediatric Leukemia: Heterogeneity in Target Modulation Activities and Cytotoxicity by Diverse Novel Therapeutic Agents

“…Even though these data are suggestive of potential compensatory mechanisms among the different isoforms, additional experimental evidence is needed to show that such a process may lead to the development of resistance to Aurora kinase inhibitors. Other mechanisms of resistance have been shown to be associated with Aurora kinase inhibition, including p53 as a regulator of translation and MDR proteins, autophagic proteins involved in the lysosome dependent degradation of cytoplasmic organelles and proteins and factors involved in cellular metabolism [35]. These proteins may be considered as targets for combined therapy with Aurora kinase inhibitors to decrease the incidence of resistance, particularly in subpopulations involved in the development of relapsed leukemia.…”

Revelation of fibroblast protein commonalities and differences and their possible roles in wound healing and tumourigenesis using co‐culture models of cells

“…For 2D‐E in pH 4–7 range, sample aliquots corresponding to 100 µg protein were processed as described previously by Hrabakova et al. (). Briefly, samples were loaded on the first dimension isoelectric focussing (IEF) for separation using active in gel rehydration of Immobiline DryStrips (18 cm pH 4–7), performed on IEF cell (Bio‐Rad) system.…”