University of Connecticut, Internal Medicine, Farmington, CT 06030, USA.
Hematology and Oncology Department Saint Francis Hospital, Hartford, CT 06105, USA.
Curr Oncol. 2020 Dec 25;28(1):196-202. doi: 10.3390/curroncol28010021.
V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.
V-RAF 鼠肉瘤病毒致癌基因同源物 B1（BRAF）突变型非小细胞肺癌（NSCLC）是一种极其罕见的肺癌形式，仅在 1%至 2%的 NSCLC 诊断患者中发现。BRAF NSCLC 传统上影响前吸烟者或现吸烟者。BRAF 突变一直是肿瘤学界特别关注的对象，因为它们为靶向治疗提供了潜力。BRAF 突变谱包括 V600 型和非 V600 型突变。BRAF V600 是一种激活突变，导致激酶活性升高和快速加速纤维肉瘤（RAF）等活性致癌蛋白过度产生。这使它们容易受到 RAF 抑制剂的靶向治疗。然而，关于 RAF 抑制剂对具有中等至低激酶活性的非激活突变（如非 V600 BRAF 突变）的疗效的证据很少。尽管已经研究了几种方法来克服 RAF 抑制剂的局限性，例如使用丝裂原活化蛋白激酶激酶（MEK）和细胞外信号调节激酶（ERK）抑制剂或 MEK 和 RAF 抑制剂的联合使用，但没有一种方法被证明对低激酶活性的非 V600 BRAF 肿瘤具有优越的疗效。我们报告了一例非吸烟者中极为罕见的 NSCLC BRAF p.T599dup 突变的病例，该病例对 RAF 和 MEK 抑制剂的靶向联合治疗有反应。该患者对通常针对高激酶活性 V600 突变的治疗反应良好。我们希望引起对非 V600 突变的更多关注，并记录它们对现有和新疗法的反应。
