OCT 11, 2018 12:00 PM PDT

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

Speaker
  • Post Doctoral Research Scholar at University of California, San Francisco
    Biography
      Khyati Shah received her Ph.D. in Molecular Pharmacology from the University of the Pacific, Stockton, California. Her graduate research was completed in the lab of Jesika Faridi, Ph.D. Her work focused on the investigation of the mechanism of Akt induced tamoxifen resistance in breast cancer.

      Currently, Khyati is the research fellow in Bandyopadhyay Lab since 2015. Her project involves investigation of the mechanism of resistance to targeted and immuno-therapy using systems biology approach. She has three-first author publications in the reputed peer-reviewed journals and 7 oral and 15 poster talks on the use of systemic genomics and proteomic approach to design rational combination therapy and to increase the durability of therapeutic response.

    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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