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Bengt Hallberg



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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-18 - Upregulation of AURKA Leads to Acquired Resistance in EML4-ALK NSCLC Cell Line (ID 2584)

      10:15 - 18:15  |  Author(s): Bengt Hallberg

      • Abstract

      Background

      Molecular targeted therapies in NSCLC often results in profound initial patient responses, these responses are short-term due to the development of acquired resistance. In an EML4-ALK NSCLC background, acquired resistance can be developed in two ways ALK dependent (ALK secondary mutations) and ALK independent (alternative oncogenic pathways). In our study, we have shown that increased expression of Aurora kinase A (AURKA) leads to acquired resistance upon treatment with ALK TKI crizotinib.

      Method

      In order to determine the mechanism for acquired resistance, we treated the EML4-ALK NSCLC cell line H2228 with increasing dose of crizotinib until cells develop resistance. RNA sequencing was performed in both parental and resistant cell lines to identify differentially expressed genes. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting.

      Result

      In this study, we describe the upregulation of AURKA gene expression leads to acquired resistance in EML4-ALK cell line H2228. The R2: genomics analysis and visualization platform (http://r2.amc.nl) revealed that high AURKA expression is associated with poor prognosis in lung adenocarcinoma patients. Based on RNA seq data, we identify upregulation of AURKA in crizotinib resistance cell line when compared to the parental cell line. The resistant cell lines were sensitive to treatment with AURKA inhibitor MLN8237 and underwent apoptosis.

      Conclusion

      Our results indicate a new mechanism to acquire resistance upon treatment with ALK TKI crizotinib. Inhibition of both ALK and AURKA activity might be beneficial for ALK TKI resistant tumors with increased AURKA gene expression/activity.