Katayama Ryohei, Friboulet Luc, Koike Sumie, Lockerman Elizabeth L, Khan Tahsin M, Gainor Justin F, Iafrate A John, Takeuchi Kengo, Taiji Makoto, Okuno Yasushi, Fujita Naoya, Engelman Jeffrey A, Shaw Alice T
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2014 Nov 15;20(22):5686-96. doi: 10.1158/1078-0432.CCR-14-1511. Epub 2014 Sep 16.
The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.
We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.
We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.
We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.
第一代间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI）克唑替尼是ALK重排非小细胞肺癌（NSCLC）患者的标准治疗药物。几种新一代ALK-TKI已进入临床，并在克唑替尼耐药患者中显示出有前景的活性。由于即使使用这些新一代ALK-TKI患者仍会复发，我们研究了对新一代ALK-TKI阿来替尼耐药的机制以及克服这种耐药性的潜在策略。
我们建立了阿来替尼耐药的细胞系模型，并分析了一名在阿来替尼治疗后复发患者的耐药肿瘤标本。我们构建了携带阿来替尼耐药性ALK突变的Ba/F3模型，并评估了其他新一代ALK-TKI在这些模型中的效力。我们在对阿来替尼获得性耐药的患者中测试了新一代ALK-TKI色瑞替尼的抗肿瘤活性。为了阐明ALK突变的构效关系，我们使用MP-CAFEE进行了计算热力学模拟。
我们从细胞系模型中鉴定出一种新的V1180L守门突变，并从对阿来替尼产生耐药性的患者中鉴定出第二种新的I1171T突变。这两种ALK突变均赋予对阿来替尼以及克唑替尼的耐药性，但对色瑞替尼和其他新一代ALK-TKI敏感。用色瑞替尼治疗该患者导致显著反应。热力学模拟表明，这两种突变均导致明显的结构改变，从而降低与阿来替尼的结合亲和力。
我们鉴定出在阿来替尼暴露后出现的两种对其他新一代ALK-TKI敏感的新ALK突变。色瑞替尼克服阿来替尼耐药突变的能力表明，多种新一代ALK-TKI序贯治疗具有潜在作用。
