Subbiah Vivek, Berry Jenny, Roxas Michael, Guha-Thakurta Nandita, Subbiah Ishwaria Mohan, Ali Siraj M, McMahon Caitlin, Miller Vincent, Cascone Tina, Pai Shobha, Tang Zhenya, Heymach John V
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
Lung Cancer. 2015 Jul;89(1):76-9. doi: 10.1016/j.lungcan.2015.04.004. Epub 2015 Apr 22.
In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.
框内融合的KIF5B（驱动蛋白家族5B基因）-RET转录本在1%-2%的非小细胞肺癌中被发现，是已知的致癌驱动因素。RET酪氨酸激酶抑制剂凡德他尼可抑制融合诱导的、不依赖锚定的生长活性。体外研究表明，凡德他尼是乳腺癌耐药蛋白（Bcrp1/Abcg2）的高亲和力底物，但不被P-糖蛋白（P-gp）转运，这限制了其血脑屏障穿透能力。一种通过用mTOR抑制剂（特别是依维莫司）调节P-gp/Abcb1和Bcrp1/Abcg2介导的外排来增强凡德他尼脑内蓄积的联合给药策略，显示可增加血脑屏障的穿透率。我们报告了首个从实验室到临床的证据，即RET抑制剂与mTOR抑制剂联合使用对脑转移的RET重排肺癌有效，也是血脑屏障穿透的首个证据。一名74岁女性，患有进展性肺腺癌（野生型EGFR且无ALK重排），前来寻求治疗方案。荧光原位杂交检测发现5'RET缺失，提示RET基因重排。由于脑部疾病进展，她参加了一项凡德他尼和依维莫司的临床试验（NCT01582191）。综合基因组分析显示，除了AKT2基因扩增外，还存在KIF5B（驱动蛋白家族5B基因）与RET的融合。经过两个周期的治疗，重复的脑部MRI显示颅内疾病负担减轻，PET/CT也显示出全身反应。有趣的是，观察到的AKT2扩增是PI3K/mTOR通路的关键组成部分，该通路的改变与靶向治疗的原发性和获得性耐药均有关。依维莫司的加入可能不仅通过其对RET基因的直接作用克服了AKT2扩增从而产生反应。我们的病例报告构成了凡德他尼联合依维莫司穿透血脑屏障的首个证据。在此背景下还需要进一步研究。
