Abstract
Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings.
Highlights
Mitotic kinases are the main proteins that coordinate accurate mitotic processing [1]
Aurora kinase A (AURKA) inhibition or knockdown was shown to induce senescence in multiple myeloma [35] and colon cancer cells [36]. These findings strongly suggest the key role of AURKA in tumorigenesis, and underscore AURKA as an attractive target for cancer therapy
Does AURKA circumvent p53 pathway, but it provides a mechanism for cancer cells to evade apoptosis by suppressing p73, an important p53 family protein [52,56]. These signaling mechanisms mediated by AURKA can promote cancer cell survival and provide a chemoresistance phenotype. These findings suggest AURKA as part of a signaling hub controlling several key pathways that regulate the hallmarks of the cancer cell network
Summary
Mitotic kinases are the main proteins that coordinate accurate mitotic processing [1]. It has been shown that AURKA can regulate and suppress GSK3β kinase activity in gastric cancer cell lines [19]. AURKA inhibition by small molecule MLN8237 as a single agent or in combination with Cisplatin or Docetaxel significantly enhanced cell death in esophageal adenocarcinoma xenograft mouse model [53,57]. Phase 1 clinical studies of the drug as a single agent demonstrate preliminary activity where 37% of patients achieved a best response of stable disease for more than 6 months in some solid tumors (colorectal cancer, chondrosarcoma, leiomyosarcoma, and liposarcoma) with modest toxicity such as nausea, stomatitis, and alopecia among other adverse effects [87].
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