Abstract：
The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient’s fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genes—the BRAF oncogene and the NF1 tumor suppressor gene—were the reason for the use of dabrafenib and trametinib treatment. The patients achieved short-term disease stabilization. This proved that coexisting mutations in these genes affect the disease course and treatment efficacy.
摘要：
第三类BRAF（B-Raf原癌基因，丝氨酸/苏氨酸激酶）变体，包括G466，D594和A581突变会导致激酶死亡或激酶活性受损。RAF(Raf原癌基因，丝氨酸/苏氨酸激酶）抑制剂在3类突变体驱动的肿瘤中抑制ERK（细胞外信号调节激酶）信号传导，因为它们优先抑制活化的BRAFV600突变体。然而,有建议认为3类突变仍然与增强的RAS/MAPK（RAS原癌基因，GTP酶/丝裂原激活蛋白激酶）激活，可能是由于其他机制，如生长因子信号的激活或并发MAPK通路突变，例如，RAS或NF1（神经纤维蛋白1）。一名75岁的男性患者患有肺鳞状细胞癌（SqCC）并向肾脏和纵隔淋巴结转移，接受了化学免疫疗法（在2％的肿瘤细胞上表达程序性细胞死亡1配体1（PD-L1））。由于伴随的骨髓增生异常综合征（MDS），化疗受到限制。并且帕博利珠单抗单药治疗持续多达7个周期.在进步的时候，进行下一代测序，c.1781A>G(p.Asp594Gly）BRAF基因中的突变，ac.1381C>T(p.Arg461Ter）NF1基因的突变，和c.37C>T（p.鉴定了FANCC基因中的Gln13Ter)突变。使用BRAF（dabrafenib）和MEK（trametinib）抑制剂联合治疗，这导致原发性病变和肺结节的部分缓解以及肾脏和骨骼中转移性病变的稳定。由于与MDS相关的骨髓抑制，5个月后停止治疗。分子背景决定了病人的命运。在BRAF基因中具有非V600突变的NSCLC患者很少应答抗BRAF和抗MEK治疗。治疗的有效性可能与NF1肿瘤抑制基因的突变有关。NF1功能的丧失导致KRAS的过度激活和含有BRAF和MEK的信号通路过度活跃,这是治疗的目标。此外，FANCC基因突变可能与MDS的发生有关。NGS技术对于我们患者的治疗资格和NSCLC病程的预测至关重要。两个基因-BRAF癌基因和NF1肿瘤抑制基因的突变是使用dabrafenib和trametinib治疗的原因。患者实现了短期疾病稳定。这证明了这些基因中共存的突变会影响病程和治疗效果。
