In vitro validation study of HER2 and HER4 mutations identified in an ad hoc secondary analysis of the LUX-Lung 8 randomized clinical trial.
In vitro validation study of HER2 and HER4 mutations identified in an ad hoc secondary analysis of the LUX-Lung 8 randomized clinical trial.
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LUX-Lung 8 随机临床试验的临时二次分析中确定的 HER2 和 HER4 突变的体外验证研究。
DOI：
10.1016/j.lungcan.2021.10.014
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发表时间：
2021
期刊：
影响因子：
5.3
通讯作者：
Mitsudomi T.
中科院分区：
文献类型：
--
作者：
Hamada A;Suda K;Koga T;Fujino T;Nishino M;Ohara S;Chiba M;Shimoji M;Takemoto T;Soh J;Uchida T;Mitsudomi T.
目的LUX-Lung 8随机试验（LL 8）证明，与厄洛替尼相比，阿法替尼治疗后肺转移性鳞状细胞癌（SCC）患者的无进展生存期（PFS）延长。LL 8的次要分析报告称，罕见HER 2/HER 4突变的存在可能是导致该结果的部分原因。携带HER 2（风险比[HR] 0.06/p值0.02）或HER 4（HR 0.21/p值未报告）突变的患者接受阿法替尼治疗后的PFS较长。然而，这些突变的生物学功能尚不清楚。Materials and MethodsTenHER 2和13 HER 4点突变，在二次分析中检测到被转导到小鼠pro-B细胞系（Ba/F3），以确定白细胞介素-3（IL-3）的依赖性和敏感性的变化，6 EGFR或泛HER酪氨酸激酶抑制剂（TKI），包括阿法替尼和厄洛替尼。使用敏感性指数，定义为50%的抑制浓度除以谷浓度的每种药物在临床推荐doses.ResultsSeven的10个Ba/F3克隆expressingHER 2 mutations和所有13个Ba/F3克隆expressingHER 4 mutations没有增长的情况下，IL-3的疗效进行了比较，表明这些突变是非致癌的。三个表达HER 2突变E395 K、G815 R或R929 W的Ba/F3克隆获得了IL-3非依赖性生长。在所有三个生产线中，阿法替尼的敏感性指数≤厄洛替尼的五分之一。其他第二代/第三代（2G/3G）TKI对表达这些HER 2突变的克隆显示出较高的疗效。结论在Ba/F3模型中，LL 8肺SCC中检测到的大多数HER 2/4突变不是致癌性的，表明HER 2/4突变的存在不是LL 8研究中阿法替尼上级结局的原因。然而，一些患者的肺SCC可能是由罕见的HER 2突变驱动的，这些患者可能从2G/3G pan-HER-TKI治疗中获益。
ObjectivesThe LUX-Lung 8 randomized trial (LL8) demonstrated a prolonged progression-free survival (PFS) in patients with metastatic squamous cell carcinoma (SCC) of the lung after treatment with afatinib compared with erlotinib. A secondary analysis of the LL8 reported that the presence of rareHER2/HER4mutations may be partly responsible for this result. Patients withHER2(hazard ratio [HR] 0.06/p-value 0.02) orHER4(HR 0.21/p-value unreported) mutations had longer PFS after treatment with afatinib. However, the biological function of these mutations is unclear.Materials and MethodsTenHER2and 13HER4point mutations that were detected in the secondary analysis were transduced into the mouse pro-B cell line (Ba/F3) to determine changes in interleukin-3 (IL-3) dependence and sensitivity to six EGFR or pan-HER tyrosine kinase inhibitors (TKIs), including afatinib and erlotinib. The efficacy of the six TKIs was compared using a sensitivity index, defined as the 50% inhibitory concentration divided by trough concentration of each drug at clinically recommended doses.ResultsSeven out of 10 Ba/F3 clones expressingHER2mutations and all 13 Ba/F3 clones expressingHER4mutations did not grow in the absence of IL-3, indicating these mutations were non-oncogenic. Three Ba/F3 clones expressing theHER2mutations E395K, G815R, or R929W acquired IL-3-independent growth. The sensitivity indices for afatinib were ≤ one-fifth of those for erlotinib in all three lines. Other second/third-generation (2G/3G) TKIs showed high efficacy against clones expressing theseHER2mutations.ConclusionsThe majority ofHER2/4mutations detected in lung SCC from LL8 were not oncogenic in the Ba/F3 models, suggesting that the presence ofHER2/4mutations were not responsible for the superior outcomes of afatinib in the LL8 study. However, SCC of the lung in some patients may be driven by rareHER2mutations, and these patients may benefit from 2G/3G pan-HER-TKI treatment.