In vivo growth inhibition elicited by afatinib and GSK2849330 in a CLU–NRG1-rearranged PDX mouse model. In vivo growth inhibition elicited by afatinib.

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In vivo growth inhibition elicited by afatinib and GSK2849330 in a CLU–NRG1-rearranged PDX mouse model. In vivo growth inhibition elicited by afatinib and GSK2849330 in a CLU–NRG1-rearranged PDX mouse model. A, A panel of PDX models was profiled by RNA-seq. An ovarian cancer PDX model, OV-10-0050, showed a high level of NRG1 mRNA expression, resulting from a novel CLU–NRG1 intragenic rearrangement (inset) where exon 2 of CLU (chromosome 8) was fused with exon 6 or NRG1 (chromosome 8) with retention of the extracellular EGF-like domain in the fusion product, as shown. B, Female BALB/c nude mice were subcutaneously implanted with CLU–NRG1-rearranged tumors and treated with afatinib at 15 mg/kg daily (QD) for 28 days, resulting in a significant inhibition of tumor growth compared with the vehicle arm (n = 6, top). The same PDX mouse model was treated with the anti-ERBB3 mAb GSK2849330 at 25 mg/kg biweekly (BIW) for 35 days, resulting in a dramatic response of complete tumor regression compared with vehicle- or IgG-treated controls (n = 10, bottom). Changes from baseline tumor volume (TV), as measured by [TV (final) − TV (initial)] × 100/TV (initial), are shown in the waterfall plots. C, Pharmacodynamic changes in tumor tissues as measured 4 hours after a single dose of treatment with afatinib, vehicle, GSK2849330, or IgG control (n = 3) are shown. Alexander Drilon et al. Cancer Discov 2018;8:686-695 ©2018 by American Association for Cancer Research