HER2 activating mutations are targets for colorectal cancer treatment.
HER2 activating mutations are targets for colorectal cancer treatment.
复制标题
DOI：
10.1158/2159-8290.cd-14-1211
复制
发表时间：
2015-08
期刊：
影响因子：
28.2
通讯作者：
Bose R
中科院分区：
文献类型：
--
作者：
Kavuri SM;Jain N;Galimi F;Cottino F;Leto SM;Migliardi G;Searleman AC;Shen W;Monsey J;Trusolino L;Jacobs SA;Bertotti A;Bose R
癌症基因组图谱项目在7%的结直肠癌患者中发现了HER2体细胞突变和基因扩增。将HER2突变S310F、L755S、V777L、V842I和L866M导入结肠上皮细胞，增加了信号通路和锚定非依赖性细胞生长，表明它们正在激活突变。将这些HER2激活突变引入结直肠癌细胞系，通过维持MAPK的磷酸化，产生了对西妥昔单抗和帕尼图单抗的耐药性。HER2突变可被低纳摩尔剂量的不可逆酪氨酸激酶抑制剂neratinib和afatinib有效地抑制。对48例西妥昔单抗耐药的四重(KRAS、NRAS、BRAF和PIK3CA)结直肠癌患者异基因移植物(PDX‘s)进行HER2基因测序，发现4例PDX存在HER2突变。HER2靶向治疗在两种PDX上进行了测试。单一HER2靶向药物(曲妥珠单抗、奈拉替尼或拉帕替尼)治疗延缓了肿瘤的生长，但曲妥珠单抗加酪氨酸激酶抑制剂的双重HER2靶向治疗可使这些HER2突变的PDX消退。
The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of colorectal cancer patients. Introduction of the HER2 mutations, S310F, L755S, V777L, V842I, and L866M, into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutations are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors, neratinib and afatinib. HER2 gene sequencing of 48 cetuximab resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) WT colorectal cancer patient-derived xenografts (PDX’s) identified 4 PDX’s with HER2 mutations. HER2 targeted therapies were tested on two PDX’s. Treatment with a single HER2 targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDX’s.