Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
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DOI：
10.1158/1078-0432.ccr-14-1385
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Fujita N
中科院分区：
文献类型：
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作者：
Katayama R;Kobayashi Y;Friboulet L;Lockerman EL;Koike S;Shaw AT;Engelman JA;Fujita N
ROS1 重排导致 ROS1 激活，具有有效的转化活性。在一项正在进行的 1 期试验中，ALK 酪氨酸激酶抑制剂 (TKI) 克唑替尼 (crizotinib) 在携带 ROS1 融合的非小细胞肺癌 (NSCLC) 患者中显示出显着的初始反应；然而，由于 ROS1 中的 G2032R 等获得性突变，癌症最终会产生克唑替尼耐药性。因此，需要了解 ROS1 重排 NSCLC 中的克唑替尼耐药机制并确定克服耐药性的治疗策略。检查了 CD74-ROS1 转化的 Ba/F3 细胞对多种 ALK 抑制剂的敏感性。通过 Ba/F3 细胞的 N-乙基-N-亚硝基脲诱变筛选 CD74-ROS1 融合中获得性 ROS1 抑制剂抗性突变。为了克服耐药突变，我们对临床实践中使用或目前正在临床试验中测试的小分子抑制剂和抗癌药物进行了高通量药物筛选。在 CD74-ROS1 突变 Ba/F3 细胞和含有 G2032R 突变 CD74-ROS1 的克唑替尼耐药患者来源癌细胞 (MGH047) 中评估了所鉴定药物的效果。我们在 ROS1 激酶结构域中发现了多个新的克唑替尼耐药突变，包括 G2032R 突变。高通量药物筛选的结果是，我们发现cMET/RET/VEGFR抑制剂卡博替尼（XL184）能有效抑制CD74-ROS1-WT以及含有Ba/F3和MGH047细胞的耐药突变体的存活。此外，卡博替尼可以克服所有新发现的二次突变产生的所有耐药性。我们开发了一个具有 ROS1 重排的 NSCLC 中对 ROS1 抑制剂获得性耐药的综合模型，并确定卡博替尼作为克服耐药性的治疗策略。
ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase 1 trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib resistance mechanisms in ROS1 rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required. The sensitivity of CD74-ROS1-transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor resistant mutations in CD74-ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high throughput drug screening with small molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74-ROS1 mutant Ba/F3 cells and crizotinib resistant patient-derived cancer cells (MGH047) harboring G2032R mutated CD74-ROS1. We identified multiple novel crizotinib resistance mutations in the ROS1 kinase domain including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74-ROS1-WT and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations. We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance.