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J.J. Haworth

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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.12 - Short-Term Culture of Patient Derived Tumor Organoids Identify Neratinib/Trastuzumab as an Effective Combination in HER2 Mutant Lung Cancer (ID 10119)

      15:45 - 17:30  |  Author(s): J.J. Haworth

      • Abstract
      • Presentation
      • Slides

      There are currently no effective targeted therapies for HER2 mutant lung cancer. Both neratinib alone or in combination with temsirolimus both have low response rates. One challenge is the lack of patient derived HER2 mutant cell line models and a platform in which to identify the most effective therapeutic strategy. Patient derived xenografts (PDXs) are emerging as an alternative tool to screen for drug efficacy, but can take months to generate and are impractical for screening of large sets of drug combinations. Here we report on a novel 3D microfluidic platform that allows for evaluating ex vivo responses to targeted therapies or targeted therapy combinations from patient derived tumor spheroids (xDOTS).

      We generated xDOTS from DFCI 359, a PDX derived from a HER2 mutant (InsYVMA) NSCLC patient under an IRB approved protocol. Tumor organoids (<100 μm and >40μm) were treated with: HER2 covalent inhibitors (neratinib, afatinib); an EGFR inhibitor (gefitinib), and combinations of HER2 inhibitors and other compounds (neratinib/trastuzumab or neratinib/temsirolimus) at known peak plasma concentrations for 3 days in our 3D microfluidic cell culture device. Live/death quantification was performed by dual labeling de-convolution fluorescence microscopy using acridine orange for live and propidium iodide for dead cells. Cell type characterization was performed by immunofluorescence. The most effective combination was used to treat the DFCI 359 PDX and a HER2 InsYVMA genetically engineered mouse model (GEMM).

      Both neratinib alone and afatinib alone, but not gefitinib, induced high degree of cell death in the DFCI 359 xDOTS. The combinations of neratinib/trastuzumab, and neratinib/temsirolimus enhanced the therapeutic benefit compared to neratinib alone, with the former combination being more effective than the latter. Using fluorescence microscopy we demonstrate that the effects are specific to the tumor cells, rather than the stromal component. We then went on to confirm these findings in a concomitant in-vivo efficacy experiment using the DFCI 359 PDX and the HER2 InsYVMA GEMM. In both in vivo models, the neratinib/trastuzumab combination led to significant tumor regressions and was superior to either single agents or the neratinib/temsirolimus combination.

      Our findings demonstrate the ability to use a 3-D in vivo microfluidic system to identify combination therapies for HER2 mutant NSCLC. Based on our studies, neratinib/trastuzumab is a promising combination for a clinical trial for HER2 mutant lung cancer.

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