Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib

BackgroundOverexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known. Methodology/Principal FindingsWe cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002. Conclusions/SignificancePatients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.背景：约三分之一的乳腺癌患者可观察到ERBB2激酶过表达，双重ERBB1/ERBB2激酶抑制剂拉帕替尼（lapatinib）近日已获批用于治疗晚期ERBB2阳性乳腺癌。近期有研究报道，在确诊的乳腺癌患者以及胃癌、结直肠癌和肺癌患者体内均检出ERBB2受体突变。此类突变可能影响拉帕替尼治疗乳腺癌的临床疗效，也可能对拉帕替尼在其他实体瘤中的应用产生潜在影响。然而，目前尚不明确拉帕替尼对临床检出的ERBB2突变的敏感性。 研究方法与主要结果：我们克隆了8种临床检出的ERBB2突变体，构建了稳定细胞系，并表征了它们对拉帕替尼及其他ERBB2抑制剂的敏感性。研究中同时发现了拉帕替尼敏感型与耐药型ERBB2突变。值得注意的是，在长期用拉帕替尼处理的野生型ERBB2（wt-ERBB2）细胞中，我们成功诱导出拉帕替尼耐药突变，这提示此类耐药突变可能在接受拉帕替尼治疗的患者体内引发继发性耐药。进一步研究发现，携带耐药突变的ERBB2对AEE788治疗具有高度耐药性，但仍对双重不可逆抑制剂CL-387785和WZ-4002保持敏感。 结论与意义：确诊时携带特定ERBB2激酶结构域突变的患者，可能无法从拉帕替尼治疗中获益。此外，继发性拉帕替尼耐药可能由激酶结构域突变引发。对于携带拉帕替尼耐药突变的乳腺癌及其他实体瘤患者，不可逆ERBB2抑制剂可作为替代治疗方案。除此之外，此类抑制剂在继发性拉帕替尼耐药的临床场景中也具有应用潜力。