Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Menoufia, Egypt.
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA; Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston; MD Anderson Cancer Network, The University of Texas MD Anderson Cancer Center, Houston, USA.
ESMO Open. 2023 Apr;8(2):100788. doi: 10.1016/j.esmoop.2023.100788. Epub 2023 Feb 24.
BRAF activation occurs as part of the mitogen-activated protein kinase (MAPK) cellular signaling pathway which leads to increased cellular proliferation and survival. Mutations in BRAF can result in unbridled activation of downstream kinases with subsequent uncontrolled cellular growth that formulate the basis for oncogenesis in multiple tumor types. Targeting BRAF by selective inhibitors has been one of the early successes in precision oncology. Agents have been explored either as monotherapy or in combination with MEK inhibition in BRAF V600-mutant pan-cancers and with EGFR inhibition in colorectal cancer. Spectrum of BRAF inhibition has evolved from being melanoma-specific to being a pan-cancer target. In this article, we review BRAF and MEK inhibitor drug development journey from tissue-specific melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer to tissue-agnostic approvals.
BRAF 激活是丝裂原活化蛋白激酶 (MAPK) 细胞信号通路的一部分，导致细胞增殖和存活增加。BRAF 突变可导致下游激酶不受控制地激活，随后发生不受控制的细胞生长，这构成了多种肿瘤类型致癌的基础。通过选择性抑制剂靶向 BRAF 是精准肿瘤学早期成功的范例之一。这些药物要么作为单一药物，要么与 MEK 抑制联合应用于 BRAF V600 突变的泛癌种，或与 EGFR 抑制联合应用于结直肠癌。BRAF 抑制的范围已从黑色素瘤特异性扩展到泛癌种靶点。在本文中，我们回顾了 BRAF 和 MEK 抑制剂的药物开发历程，从组织特异性黑色素瘤、非小细胞肺癌和间变性甲状腺癌到组织不可知的批准。
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