AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy

Jordi Bertran-Alamillo, Valérie Cattan, Marie Schoumacher, Jordi Codony-Servat, Ana Giménez-Capitán, Frédérique Cantero, Mike Burbridge, Sonia Rodríguez, Cristina Teixidó, Ruth Roman, Josep Castellví, Silvia García-Román, Carles Codony-Servat, Santiago Viteri, Andrés-Felipe Cardona, Niki Karachaliou, Rafael Rosell and Miguel-Angel Molina-Vila ()
Additional contact information
Jordi Bertran-Alamillo: Quiron Dexeus University Hospital
Valérie Cattan: Institut de Recherches Internationales Servier
Marie Schoumacher: Institut de Recherches Internationales Servier
Jordi Codony-Servat: Quiron Dexeus University Hospital
Ana Giménez-Capitán: Quiron Dexeus University Hospital
Frédérique Cantero: Institut de Recherches Internationales Servier
Mike Burbridge: Institut de Recherches Internationales Servier
Sonia Rodríguez: Quiron Dexeus University Hospital
Cristina Teixidó: Quiron Dexeus University Hospital
Ruth Roman: Quiron Dexeus University Hospital
Josep Castellví: Quiron Dexeus University Hospital
Silvia García-Román: Quiron Dexeus University Hospital
Carles Codony-Servat: Quiron Dexeus University Hospital
Santiago Viteri: Quiron-Dexeus University Hospital
Andrés-Felipe Cardona: Fundacion Santa Fe de Bogotá
Niki Karachaliou: Quiron-Dexeus University Hospital
Rafael Rosell: Quiron Dexeus University Hospital
Miguel-Angel Molina-Vila: Quiron Dexeus University Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.

Date: 2019
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DOI: 10.1038/s41467-019-09734-5

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