Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the <i>RB1</i> Tumor Suppressor Gene

Gong, Xueqian; Du, Jinyan; Parsons, Stephen H.; Merzoug, Farhana F.; Webster, Yue; Iversen, Philip W.; Chio, Li-Chun; Horn, Robert D. Van; Lin, Xi; Blosser, Wayne; Han, Baek Soo; Jin, Shaoling; Yao, Sufang; Bian, Huimin; Ficklin, Chris; Fan, Li; Kapoor, Avnish; Antonysamy, Stephen; Nulty, Ann Mc; Froning, Karen; Manglicmot, Danalyn; Pustilnik, Anna; Weichert, Kenneth; Wasserman, S.R.; Dowless, Michele; Marugán, Carlos; Baquero, Carmen; Lallena, Marı́a José; Eastman, Scott W.; Hui, Yu‐Hua; Dieter, Matthew Z.; Doman, Thompson N.; Chu, Shaoyou; Qian, Hui-Rong; Ye, Xiang S.; Barda, David A.; Plowman, Gregory D.; Reinhard, Christoph; Campbell, Robert M.; Henry, James R.; Buchanan, Sean G.

doi:10.1158/2159-8290.cd-18-0469

Cited by 162 publications

(139 citation statements)

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“…The methods for generating resistant cell lines were described previously. 34 Briefly, MDA-MB-361, T47D and MCF-7 ER+ breast cancer cell lines were used to derive variants with acquired resistance to abemaciclib or palbociclib. T47D (HTB-133), MCF-7 (HTB-22) and MDA-MB-361 (HTB-27) were purchased from The American Type Culture Collection (ATCC).…”

Section: Methodsmentioning

confidence: 99%

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

Wander

Cohen

Gong

et al. 2019

Preprint

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AbstractClinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.

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Section: Methodsmentioning

confidence: 99%

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

Wander

Cohen

Gong

et al. 2019

Preprint

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“…Recent studies implicate Aurora kinases (AURKA or AURKB) that regulate mitotic spindle assembly and chromosome segregation as alternative therapeutic targets. Independent CRISPR/Cas9 (Oser et al, 2019) and drug screening assays (Gong et al, 2019) using Rb1-deficient classical SCLC cell lines simultaneously identified a unique dependence upon AURK for survival. In these studies, AURK inhibitors potently suppressed the growth of Rb1-negative SCLC cells but had no effect on Rb1-positive lung cancer cells (including the EGFR mutant cell lines H1975 and PC9).…”

Section: Targeting Unique Cell Cycle Vulnerabilities Created By Rb1 Lossmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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“…In addition, cell death may not necessarily occur through inhibition of a canonical Aurora B kinase signaling. Recently, a noncanonical dependency for Aurora B kinase function was described for SCLC cell lines in which the RB tumor suppressor function is lost (24). In these cells, Aurora B kinase inhibition induced rapid cell death due to a dependence on an alternate checkpoint function.…”

Section: Discussionmentioning

confidence: 99%

Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma

Floc’h

Ashton

Ferguson

et al. 2019

Molecular Cancer Therapeutics

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Barasertib (AZD1152), a pro-drug of the highly potent and selective Aurora B kinase inhibitor AZD2811, showed promising clinical activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients administered as a 4-day infusion. To improve potential therapeutic benefit of Aurora B kinase inhibition, a nanoparticle formulation of AZD2811 has been developed to address limitations of repeated intravenous infusion. One of the challenges with the use of nanoparticles for chronic treatment of tumors is optimizing dose and schedule required to enable repeat administration to sustain tumor growth inhibition. AZD2811 gives potent cell growth inhibition across a range of DLBCL cells lines in vitro. In vivo, repeat administration of the AZD2811 nanoparticle gave antitumor activity at half the dose intensity of AZD1152. Compared with AZD1152, a single dose of AZD2811 nanoparticle gave less reduction in pHH3, but increased apoptosis and reduction of cells in G1 and G 2 -M, albeit at later time points, suggesting that duration and depth of target inhibition influence the nature of the tumor cell response to drug. Further exploration of the influence of dose and schedule on efficacy revealed that AZD2811 nanoparticle can be used flexibly with repeat administration of 25 mg/kg administered up to 7 days apart being sufficient to maintain equivalent tumor control. Timing of repeat administration could be varied with 50 mg/kg every 2 weeks controlling tumor control as effectively as 25 mg/kg every week. AZD2811 nanoparticle can be administered with very different doses and schedules to inhibit DLBCL tumor growth, although maximal tumor growth inhibition was achieved with the highest dose intensities.

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Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene

Cited by 162 publications

References 52 publications

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma

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