Role of Erbb3 kinase activity in colorectal tumorigenesis.

该提案的总体目标是确定Erbb 3激酶是否在结肠直肠癌中起关键作用。 肿瘤发生，并测试是否具有致癌Erbb 3突变的结直肠癌对抗PD 1的反应更好 抗体的Erbb 3是EGFR受体蛋白酪氨酸激酶家族的一员，在多种肿瘤细胞中发生突变。 人类癌症，包括结肠直肠癌（CRC）。与其他EGFR家族成员不同， Erbb 3被认为是一种没有酶活性的假激酶。尽管有充分的证据表明Erbb 3 在肿瘤发生中起致癌作用，Erbb 3激活驱动肿瘤发生的机制是 大部分未知。我们做出了范式转变的发现，即Erbb 3的假激酶结构域是一个 丝氨酸/苏氨酸（S/T）激酶，其通过质膜结构域中丝氨酸位点的磷酸化而活化，和 其激酶活性是异种移植物和基因工程小鼠中稳健肿瘤生长所必需的 模型此外，我们发现Erbb 3激酶死亡突变体损害干扰素-γ（IFN-γ）诱导的PD-L1， CRCs中的表达。有趣的是，在小鼠结肠癌细胞系中敲入致癌Erbb 3突变， 使其对抗PD 1抗体治疗敏感。在这里，我们提出了两个目标，以确定Erbb 3的作用 S/T激酶在（1）结直肠肿瘤发生和（2）结直肠癌对免疫检查点的反应中的作用 抑制剂的本研究的成功完成为Erbb 3突变体的靶向治疗奠定了基础 具有Erbb 3激酶抑制剂和/或免疫检查点抑制剂的CRC。考虑到Erbb 3的异常激活 导致对各种癌症治疗的耐药性，包括乳腺癌中的赫赛汀和肺癌中的EGFR抑制剂 癌症，我们的研究将对癌症治疗产生广泛的影响。

The overarching goals of this proposal are to determine if Erbb3 kinase plays a critical role in colorectal tumorigenesis and to test if colorectal cancer with oncogenic Erbb3 mutations respond better to anti-PD1 antibody. Erbb3, a member of the EGFR family of receptor protein tyrosine kinases, is mutated in a variety of human cancers including colorectal cancer (CRC). Unlike other EGFR family members, the kinase domain of Erbb3 is thought to be a pseudo-kinase without enzymatic activity. Although it is well documented that Erbb3 plays an oncogenic role in tumorigenesis, the mechanisms by which Erbb3 activation drives tumorigenesis are largely unknown. We made the paradigm-shifting discovery that the pseudo-kinase domain of Erbb3 is a serine/threonine (S/T) kinase activated by phosphorylation of a serine site in the juxatomembrane domain, and that its kinase activity is required for robust tumor growth in both xenograft and genetically engineered mouse models. Moreover, we found that a Erbb3 kinase-dead mutant impairs interferon-γ (IFN-γ)-induced PD-L1 expression in CRCs. Interestingly, knockin of an oncogenic Erbb3 mutation in mouse colon cancer cell lines renders them sensitive to anti-PD1 antibody therapy. Here we propose two aims to determine the role of Erbb3 S/T kinase in (1) colorectal tumorigenesis and (2) the response of colorectal cancers to immune checkpoint inhibitors. Successful completion of our proposed studies will lay a solid foundation for targeting Erbb3 mutant CRCs with Erbb3 kinase inhibitors and/or immune checkpoint inhibitors. Given that aberrant activation of Erbb3 causes resistance to various cancer therapies including Herceptin in breast cancer and EGFR inhibitors in lung cancer, the impact of our studies will have a broad impact on cancer therapy.