洛那法尼治疗RAS突变

一、洛那法尼

洛那法尼Lonafarnib (Sch66336) 是一种有效的，具有口服活性的法尼基蛋白转移酶 (FPTase) 抑制剂，作用于 H-ras，K-ras 和 N-ras，IC50 分别为 1.9 nM，5.2 nM 和 2.8 nM
（1）CAS号：193275-84-2

（2）分子量：638.82

（3）用法用量：可以参考《Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma》这篇论文讲到的洛那法尼联合紫杉醇治疗非小细胞肺癌的二期临床试验的剂量，即每天两次，每次100毫克。要注意的是，洛那法尼抗癌剂量不同于治疗儿童早衰症的剂量。

（4）常见副作用：疲劳、厌食、恶心、意识模糊、脱水、肌无力、抑郁、头痛和呼吸困难。


二、洛那法尼治疗ras突变的作用机制

洛那法尼治疗 ras突变的作用机制在于加速ras蛋白的失活和降解。洛那法尼抑制法尼基转移酶。ras蛋白是要在癌细胞细胞质膜上定位的，如果离开质膜，ras蛋白就会失活、就会加速降解。Ras蛋白的法尼基化是Ras蛋白膜定位所必需的，这是其生物活性的先决条件。法尼基蛋白转移酶(FPTase)是ras蛋白法尼基化的关键；抑制FPTase，就会加速ras蛋白失活和降解，从而抑制ras蛋白的促癌作用。

洛那法尼治疗ras突变的作用机制与 Sotorasib等直接抑制kras的药物并不相同，因此耐药机制上也大概率是不同的，用过Sotorasib等直接抑制kras的药物后再用洛那法尼发生交叉耐药的概率比较小。


三、洛那法尼与紫杉醇有很强的协同作用

《Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma》
 
Methods: Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle.
 
Results: A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%).
 
Conclusions: Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.

可以把紫杉醇换成药效更强的白紫。当然如果能先做minipdx检测或者类器官药敏检测，测试一下这个方案的效果后再用那更好。