Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China; Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Cancer Treat Rev. 2019 Dec;81:101907. doi: 10.1016/j.ctrv.2019.101907. Epub 2019 Oct 14.
The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.
RAS 衍生的丝裂原活化蛋白激酶（MAPK）信号通路的异常激活在多种恶性肿瘤的发生中起着重要作用。其原因通常是上游激活突变，包括丝裂原活化蛋白激酶激酶 1/2（MEK1/2）。作为致癌突变，MEK1 突变已在多种恶性肿瘤中观察到，包括黑色素瘤、组织细胞肿瘤、结直肠癌和肺癌。目前，根据 FDA 的批准，高度选择性 MEK1/2 抑制剂 trametinib 的使用仅限于 BRAF 突变。因此，我们认为这是一个值得研究的问题，即是否存在 MEK1 突变的恶性肿瘤对 trametinib 的治疗敏感。本综述讨论了 MEK1 突变的功能，检索了各种恶性肿瘤中 MEK1 突变的频率和分布，并综述了关于 trametinib 治疗 MEK1 突变的细胞系或患者的基础实验和临床病例报告。大多数研究表明，tramet inib 对携带 MEK1 突变的细胞或肿瘤患者有效，这表明 MEK1 突变可能是 trametinib 治疗的潜在指征。此外，还报道了在 trametinib 治疗中观察到耐药性，表明不同的 MEK1 突变可能对 trametinib 有不同的反应，需要进一步研究以区分哪些 MEK1 突变适合 trametinib 治疗，哪些不适合。
