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A. Wrona

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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI30.08 - ROS1 Resistance to Crizotinib Is Mediated by an Activating Mutation in c-KIT (ID 2244)

      18:30 - 20:00  |  Author(s): A. Wrona

      • Abstract
      • Presentation
      • Slides

      Non-small cell lung cancer (NSCLC) patients with ROS1 chromosomal rearrangement benefit from treatment with the ROS1 inhibitor crizotinib with remarkable response rates and durable disease control. Similar to ALK and EGFR mutant NSCLC treated with targeted kinase inhibitors, disease progression inevitably occurs due to acquired resistance either by mutation within the kinase domain of ROS1 or via bypass signaling. However, limited data exists on the spectrum of resistance mechanisms in ROS1+ NSCLC. Here report on a novel bypass mechanism for ROS1 resistance discovered in a ROS1+ tumor sample from patient with acquired resistance to crizotinib in which an activating mutation in the KIT receptor (p.D816G) desensitize ROS1 cells to crizotinib inhibition.

      Patients with ROS1+ NSCLC treated with crizotinib who developed acquired resistance underwent biopsy of a progressing tumor. Tumor samples were analyzed for potential resistance mechanisms. Assessment of mutations within the ROS1 kinase domain was accomplished by direct sequencing of exons 35 thru exon 42 of ROS1 from genomic DNA isolated from FFPE tissue. The SNaPshot® Multiplex System was used to profile additional tumor related genes for mutations. The ROS1 rearranged cell lines, HCC78 and CUTO-2, were transduced with lentivirus to generate ectopic expression of the KIT[D816G] cDNA. Cell proliferation was assessed by an MTS assay and cellular signaling was measured by western blot analysis.

      Sequencing of the patient’s post crizotinib sample showed no mutation in the ROS1 kinase domain. Additional mutational profiling by SNaPshot® revealed the acquisition of a KIT[D816G] mutation in the post-crizotinib sample that was not present in the pre-crizotinib tumor sample. HCC78 and CUTO-2 ROS1+ cell lines expressing the KIT[D816G] mutation were refractory to crizotinib by both cell proliferation assays and analysis of downstream signaling pathways. Both ROS1 and KIT activity had to be inhibited in order to suppress downstream signaling and proliferation in these cells.

      Activation of KIT by a gain-of-function mutation is a novel mechanism of resistance to crizotinib in ROS1 rearranged NSCLC. This bypass-signaling pathway serves as a ROS1 independent mechanism of progression, similarly to previously identified EGFR or RAS signaling pathways, and can potentially be targeted by KIT inhibitors.

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