Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
School of Biotechnology, Kalinga Institute of Industrial Technology, Odisha, 751024, India.
Sci Rep. 2019 Dec 11;9(1):18793. doi: 10.1038/s41598-019-55208-5.
Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to erlotinib by carrying out whole exome sequencing, quantitative proteomic and phosphoproteomic profiling. We observed amplification of several genes including AXL kinase and transcription factor YAP1 resulting in protein overexpression. We also observed expression of constitutively active mutant MAP2K1 (p.K57E) in erlotinib resistant SCC-R cells. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. We demonstrate that erlotinib-resistant cells are sensitive to MAPK pathway inhibition. This study revealed multiple genetic, proteomic and phosphoproteomic alterations associated with erlotinib resistant SCC-R cells. Our data indicates that therapeutic targeting of MAPK pathway is an effective strategy for treating erlotinib-resistant HNSCC tumors.
表皮生长因子受体（EGFR）靶向治疗在头颈部鳞状细胞癌（HNSCC）患者中尽管存在过度表达，但疗效有限。鉴定与 EGFR-TKIs（如厄洛替尼）获得性耐药相关的分子机制仍然是一个未满足的需求和治疗挑战。在这项研究中，我们采用了综合的多组学方法，通过进行全外显子测序、定量蛋白质组学和磷酸蛋白质组学分析，描绘了与厄洛替尼获得性耐药相关的机制。我们观察到包括 AXL 激酶和转录因子 YAP1 在内的几个基因的扩增，导致蛋白过表达。我们还观察到在厄洛替尼耐药 SCC-R 细胞中存在组成性激活的 MAP2K1（p.K57E）突变。对基因组、蛋白质组和磷酸蛋白质组数据的综合分析揭示了 SCC-R 细胞中 MAPK 通路及其下游靶标的改变。我们证明厄洛替尼耐药细胞对 MAPK 通路抑制敏感。这项研究揭示了与厄洛替尼耐药 SCC-R 细胞相关的多种遗传、蛋白质组学和磷酸蛋白质组学改变。我们的数据表明，针对 MAPK 通路的治疗靶向是治疗厄洛替尼耐药 HNSCC 肿瘤的有效策略。
