OCT 11, 2018 12:00 PM PDT

Aurora Kinase A Drives The Evolution of Resistance to Third Generation EGFR Inhibitors in Lung Cancer

Speaker

Abstract

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of pre-existing subclones, remains unclear. In EGFR-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires AURKA activity. Non-genetic resistance through the activation of AURKA by its co-activator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in pre-clinical models. Treatment induced activation of AURKA was associated with resistance to EGFR inhibitors in-vitro, in-vivo and in individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA driven residual disease and acquired resistance.
 

Learning Objectives:

1. Describe pathways of EGFR-TKI resistance mechanisms.
2. Approaches to identify novel targets in EGFR-TKI resistance patients.


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OCT 11, 2018 12:00 PM PDT

Aurora Kinase A Drives The Evolution of Resistance to Third Generation EGFR Inhibitors in Lung Cancer



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