Abstract 1957: Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer
Authors: Shah Khyati N. , Bhatt Roma , Rotow Julia , Rohrberg Julia , Olivas Victor , Hemmati Golzar Golzar , Krings Gregor , Haringsma Henry J. , Simmons Andrew D. , Harding Thomas C. , Goga Andrei , Blakely Collin , Bivona Trever , Bandyopadhyay Sourav 
Published: August 2018

With the advent of precision medicine, EGFR inhibitors are a major breakthrough in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Although these EGFR-TKI therapies often elicit profound initial therapeutic responses, their effects are transient due to residual disease. This residual disease and subsequent disease progression occurs through tumor evolution and molecular drivers behind the formation, maintenance and evolution of residual disease and acquired resistance have remained elusive. Although in many cases, pre-existing clones with bona fide genetic resistance have been identified, majority of patients have undetectable resistance causing genetic alterations, suggesting that nongenetic alterations may drive altered cell state and signaling associated with EGFR inhibitor resistance. Using EGFR mutant lung cancer cells, we developed several in vitro models of acquired resistance to third-generation EGFR-TKI inhibitors, osimertinib and rociletinib, and a chemical screen revealed that Aurora kinase inhibitors are highly synergistic when combined with third-generation EGFR inhibitors. Resistant cells harbored high activation of AURKA mediated by upregulation of its co-activator protein TPX2. In in vitro and in vivo models of acquired resistance, the combination induced potent cell death by reactivating BIM-mediated apoptosis. We found that tumors from patients progressing on first- and third-generation EGFR TKIs often harbored high levels of TPX2, indicating that AURKA is likely activated and driving resistance in a significant fraction of EGFR-mutant lung cancers. By tracking the kinetics of AURKA activation, we tested if AURKA activity is required for the formation and maintenance of residual cells leading to acquired resistance. In our sensitive in vitro models, either single-agent EGFR-TKI, MLN8237 or the combination enhanced the magnitude of response and forestalled the emergence of resistance as compared to monotherapies. We tested the combination in an EGFR L858R patient-derived xenograft (PDX) tumor model generated from a residual disease surgical specimen. In this PDX the combination robustly impaired tumor growth compared to both single agents alone and in most cases induced tumor regression This novel synthetic lethal interaction between EGFR TKIs and Aurora kinase inhibitors has important implications for the development of new treatment strategies for third-generation EGFR-TKI. These results invite a paradigm aimed at preventing the emergence of resistance.

Citation Format: Khyati N. Shah, Roma Bhatt, Julia Rotow, Julia Rohrberg, Victor Olivas, Golzar Golzar Hemmati, Gregor Krings, Henry J. Haringsma, Andrew D. Simmons, Thomas C. Harding, Andrei Goga, Collin Blakely, Trever Bivona, Sourav Bandyopadhyay. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1957.