An Integrated Genomic Approach to Identify Predictive Biomarkers of Response to the Aurora Kinase Inhibitor PF-03814735

Abstract

PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers of drug sensitivity, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines were very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735. Whereas RB1 inactivation, intact CDKN2A/p16, and normal CCND1/Cyclin D1 status are hallmarks of SCLC, activation or amplification of any of the three Myc genes (MYC, MYCL1, and MYCN) clearly differentiated cell line sensitivity within the SCLC panel. By contrast, we found that expression of Aurora A and B were weak predictors of response. We observed a decrease in histone H3 phosphorylation and polyploidization of sensitive lines, consistent with the phenotype of Aurora B inhibition. In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. Altogether our results suggest that SCLC and other malignancies driven by the Myc family genes may be suitable indications for treatment by Aurora B kinase inhibitors.

Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

“…However, the RB1 protein expression was not related to the in vivo response of the AS703569 inhibitor in this study, which is in line with previous reports showing that RB1 status alone does not correlate with sensitivity to Aurora kinase inhibitors in vivo (21,30). The finding that Aurora kinase genes A and B were highly expressed in breast cancer xenografts is consistent with previous works that showed high level of these genes in aggressive breast cancers than in benign tumors (19).…”

“…This is consistent with other preclinical studies showing that Aurora kinases inhibitors alone do not induce tumor regression in solid cancers (10,21,(31)(32)(33). Treatment with the Aurora kinase inhibitors PF-03814735 and MK-0457 delayed the growth of colon and ovarian xenografts (31,32).…”

“…A high AURKB expression was correlated to in vivo response to AS703569. A recent study showed that expression of Aurora A and B in lung cancer cell lines were weak predictors of response to Aurora kinase inhibitor PF-03814735 (21). Interestingly, the same authors reported a higher response to PF-03814735 in lung tumors with amplified or overexpressed MYC.…”

“…2C). The expression of the Myc oncogene was also determined as possible factor related to the resistance to Aurora kinase inhibitors (21). Results showed that AURKA and AURKB genes were highly expressed (C t $ 26) in all xenograft models, showing increased expression of AURKB in low-responder/resistant models compared with responders (P ¼ 0.0385, unpaired t test; Fig.…”

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

“…As reviewed recently (24), an estimated 30 small-molecule inhibitors of Aurora kinases are currently undergoing preclinical and clinical evaluation (25)(26)(27)(28)(29)(30)(31). A number of these compounds are pan-Aurora kinase inhibitors that show inhibitory activity against both AAK and Aurora B kinase (ABK), as well as, in some cases, Aurora C kinase.…”