Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo

Abstract

Small cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib with IC50 values of < 50 nM and > 75% growth inhibition at 100 nM. Growth inhibition correlated with cMYC amplification (p = 0.018) and cMYC gene expression (p = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (p = 0.042). In vivo the barasertib inhibited the growth of xenografts established from a SCLC line which had high cMYC gene expression, no cMYC amplification and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated.

BRAFV600Einduces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

“…Selective inhibitors of AURKB, but not GPR3, have been described. Two BRAF V600E human melanoma cultures -one established line (501MEL) and one derived from a low passage patient-derived xenograft tumor (HCIMel019) -were therefore treated with the selective AURKB inhibitor, Barasertib (40). Both cultures were highly sensitive to the compound, consistent with a previous report ( Fig.…”

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…MYC amplification in SCLC tumors is associated with shortened survival (64). Of major potential therapeutic importance, inhibition of AURKA and AURKB selectively inhibit growth of myc family over-expressing SCLC cell lines and causes polyploidy (11,65).…”

Family matters: How MYC family oncogenes impact small cell lung cancer

“…In recent years, exploiting synthetic lethality has emerged as a promising approach to overcome such limitations, and several examples demonstrate that this may be a viable option for treatment of MYC-driven tumors. In MYC-driven SCLC, we and others identified Aurora kinases (AURK) as promising synthetic lethal targets, 9,10,111,112 which also emerged as potential candidate targets in other MYC-driven tumors. 99,113,114 An elegant explanation for the activity of Aurora kinase inhibitors in MYCN-amplified neuroblastoma is the observation that Aurora kinase A (AURKA) binds to the MYCN/FBXW7 complex, reduces K48-linked ubiquitination of MYCN, and thus increases MYCN protein half-life.…”