Human estrogen receptor positive cancer cells have mutations and make an excess of the HER2 protein and are far more aggressive than others cancers. Neratinib, an irreversible tyrosine kinase inhibitor is used to treat HER2 positive cancers. Neratinib targets HER2 and blocks its signal transduction resulting in inhibition of cell proliferation and induction of apoptosis without any information about the molecular mechanism involved. To understand the underlying molecular mechanism transcriptome analysis was carried out in normal vs cancer induced SWR/J nude mice. Cancer was induced in SWR/J nude mice with intraperitoneal injection of 5 × 10⁶ SKBR3 cells for 14 days. Histopathology confirmed the induction of cancer in liver and kidney after the tumor size was at least 0.5 cm. Genome wide Mouse U133 Array was used to analyze the effect of neratinib treatment on cancer. Validation of expression was done by qPCR and ELISA. Microscopic examination revealed that neratinib treatment has potential effects on cancerous liver. Transcriptome expression profiling showed 1481 transcripts differentially expressed by neratinib treatment. Transcriptome Analysis Console (TAC) showed that 532 upregulated transcripts were exclusively belonging to cell cycle, inflammation, olfaction, oxidative stress, HER, and EGFR1 while 949 downregulated transcripts were involved in immunology, drug resistance such as histocompatibility, T cell receptors, and immunoglobulins. The differentially expressed genes were considered significant under the criteria of an adjusted p-value < 0.02 and log2 ratios ≥ 1.0 and/or log2 ratios ≤ − 1.0 means two Fold change. qPCR assay and ELISA analysis was used to validate few genes involved in apoptosis and proliferation. This study provides new insights into the neratinib’s mode of action by cyclin-dependent kinase inhibitor-3 and calcium-activated chloride channel 3 as markers for treatment progress.

人类雌激素受体阳性癌细胞具有突变并产生过量的HER2蛋白，并且比其他癌症更具侵略性。Neratinib是一种不可逆的酪氨酸激酶抑制剂，用于治疗HER2阳性癌症。奈拉替尼靶向HER2并阻断其信号转导，从而导致细胞增殖抑制和凋亡诱导，而无需任何有关所涉及的分子机制的信息。为了理解潜在的分子机理，在正常与癌症诱导的SWR / J裸鼠中进行了转录组分析。腹膜内注射5×10 ⁶在SWR / J裸鼠中诱发癌症SKBR3细胞持续14天。组织病理学证实，在肿瘤大小至少为0.5 cm后，肝癌和肾癌被诱导。全基因组小鼠U133阵列用于分析neratinib治疗对癌症的影响。表达的验证通过qPCR和ELISA进行。显微镜检查显示，neratinib治疗对肝癌具有潜在的影响。转录组表达谱显示了纳拉替尼治疗差异表达的1481个转录本。转录组分析控制台（TAC）显示532个上调的转录本仅属于细胞周期，炎症，嗅觉，氧化应激，HER和EGFR1，而949个下调的转录本与免疫学，组织相容性，T细胞受体和免疫球蛋白等药物抗性有关。在调整的p值<0.02和log2比率≥1.0和/或log2比率≤− 1.0的标准下，差异表达的基因被认为具有重要意义。使用qPCR分析和ELISA分析来验证与凋亡和增殖有关的少数基因。这项研究通过细胞周期蛋白依赖性激酶抑制剂3和钙激活的氯离子通道3作为治疗进展的标志物，为neratinib的作用方式提供了新的见解。