受体酪氨酸激酶 ERBB 家族的遗传变化可作为 ERBB 抑制剂药物的致癌驱动事件和预测生物标志物。 ERBB3 是该家族的假激酶成员，尽管缺乏完全活性的激酶结构域，但以其作为与 ERBB2 的异二聚体复合物的有效信号传导活性而闻名。先前的研究已经鉴定出很少的转化性 ERBB3 突变，而在不同癌症类型中观察到的数百种不同体细胞 ERBB3 变异中的绝大多数仍然具有未知的意义。在这里，我们描述了对数千个 ERBB3 突变的转化潜力进行平行的无偏见功能遗传学筛选。该筛选基于先前描述的 iSCREAM（激活突变的体外筛选）平台，并在 ERBB3/ERBB2 异二聚体背景下解决 ERBB3 假激酶信号传导，鉴定出 18 个命中突变。 Ba/F3、NIH 3T3 和 MCF10A 细胞背景中的验证实验表明，存在先前已知和未知的转化 ERBB3 错义突变，这些突变要么作为单一变体，要么以顺式形式成对组合发挥作用。使用曲妥珠单抗、帕妥珠单抗和来那替尼进行的药物敏感性测定表明了转化 ERBB3 变体的可操作性。© 2024。作者。

Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.© 2024. The Author(s).