Abstract：
HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M. Patients whose tumor expressed the HER3 V104L variant had a reduced probability of overall survival compared to patients lacking a HER3 mutation whereas we did not find a statistically significant difference in overall survival of various cancer patients with the HER3 V104M mutation. Our data showed that HER2 inhibitors suppressed cell growth of HCC1569HER3KO cells stably expressing the HER3-V104L mutation. Cancer cell lines (SNU407, UC15 and DV90) with endogenous HER3-V104M mutation showed reduced cell proliferation and p-HER2/p-ERK1/2 expression with HER2 inhibitor treatment. Knock down of HER3 abrogated cell proliferation in the above cell lines which were overall more sensitive to the ERK inhibitor SCH779284 versus PI3K inhibitors. HER3-V104L mutation stabilized HER3 protein expression in COS7 and SNUC5 cells. COS7 cells transiently transfected with the HER3-V104L mutation in the presence of HER binding partners showed higher expression of p-HER3, p-ERK1/2 versus HER3-WT in a NRG-independent manner without any change in AKT signaling. Overall, this study shows the clinical relevance of the HER3 V104L and the V104M mutations and its response to HER2, PI3K and ERK inhibitors.
摘要：
取决于癌症类型,HER3在~2%-10%的癌症中突变。我们发现HER3-V104L突变从HER3KOHER2+HCC1569乳腺癌细胞中通过慢病毒转导引入的患者衍生突变激活，其中内源性HER3被CRISPR/Cas9消除。与表达野生型HER3或HER3-V104M的细胞相比,表达HER3-V104L的细胞显示更高的p-HER3和p-ERK1/2表达。与缺乏HER3突变的患者相比，肿瘤表达HER3V104L变体的患者的总体生存率降低，而我们没有发现具有HER3V104M突变的各种癌症患者的总体生存率有统计学上的显着差异。我们的数据显示HER2抑制剂抑制稳定表达HER3-V104L突变的HCC1569HER3KO细胞的细胞生长。具有内源性HER3-V104M突变的癌细胞系(SNU407、UC15和DV90)显示用HER2抑制剂处理的细胞增殖和p-HER2/p-ERK1/2表达降低。与PI3K抑制剂相比,敲低HER3消除了对ERK抑制剂SCH779284总体更敏感的上述细胞系中的细胞增殖。HER3-V104L突变稳定了COS7和SNUC5细胞中HER3蛋白的表达。在HER结合配偶体存在下瞬时转染HER3-V104L突变的COS7细胞以不依赖NRG的方式显示p-HER3、p-ERK1/2相对于HER3-WT的更高表达,而AKT信号传导没有任何变化。总的来说,本研究显示了HER3V104L和V104M突变的临床意义及其对HER2,PI3K和ERK抑制剂的反应.
