Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer

Abstract

Lung cancer is one of the most aggressive malignancies, classified into two major histological subtypes: non-small cell lung cancer (NSCLC), that accounts for about 85% of new diagnosis, and small cell lung cancer (SCLC), the other 15%. In the case of NSCLC, comprehensive genome sequencing has allowed the identification of an increasing number of actionable targets, which have become the cornerstone of treatment in the advanced setting. On the other hand, the concept of oncogene-addiction is lacking in SCLC, and the only innovation of the last 30 years has been the introduction of immune checkpoint inhibitors in extensive stage disease. Dysregulation of cell cycle is a fundamental step in carcinogenesis, and Aurora kinases (AURKs) are a family of serine/threonine kinases that play a crucial role in the correct advance through the steps of the cycle. Hyperexpression of Aurora kinases is a common protumorigenic pathway in many cancer types, including NSCLC and SCLC; in addition, different mechanisms of resistance to anticancer drugs rely on AURK expression. Hence, small molecule inhibitors of AURKs have been developed in recent years and tested in several malignancies, with different results. The aim of this review is to analyze the current evidences of AURK inhibition in lung cancer, starting from preclinical rationale to finish with clinical trials available up to now.

Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives

“…Additionally, c-Myc expression and mutations were identified as potential predictive biomarkers of alisertib. The disease control rate, defined as the combination of complete response, partial response, and stable disease lasting at least 8 weeks, was significantly higher with alisertib/paclitaxel compared to placebo/paclitaxel (55% versus 33%) in the subgroup of resistant or refractory patients efficacy [118]. Among c-Myc-positive patients, the median progression-free survival was 4.64 months with alisertib/paclitaxel, whereas it was 2.27 months with placebo/paclitaxel.…”

P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation

“…Overexpression of Aurora kinases (AURKs) is a prevalent protumorigenic pathway in numerous cancer types, including SCLC [ 41 ]. In particular, in p53-deficient cells, the protumorigenic effects of the AURKs are even augmented [ 42 ].…”

“…The promising activity of alisertib/paclitaxel in relapsed or refractory SCLC was confirmed by the 3.2 months median progression-free survival (mPFS) for alisertib/paclitaxel compared to 2.17 months for placebo/paclitaxel (hazard ratio (HR) = 0.77) [ 45 ]. Preliminary clinical trials revealed significant indications of AURK inhibitors’ effectiveness, especially when combined with taxanes [ 41 ], but these findings require validation through phase III randomized trials.…”

Actionable Driver Events in Small Cell Lung Cancer

“…Additionally, Alisertib (MLN8237), a selective inhibitor of AURKA, has demonstrated improvement in PFS when combined with paclitaxel compared to paclitaxel alone in patients with SCLC tumors positive for C-MYC [ 87 ]. As a caveat, Aurora K inhibitor effectiveness and safety must be carefully validated in phase 3 clinical trials, as many patients, despite showing an initial good response, have had to discontinue treatment due to tumor progression or adverse effects, particularly those linked to blood malignancies [ 88 ].…”