Targeting RET-rearranged non-small-cell lung cancer: future prospects.

IF 5.1 Q1 ONCOLOGY Lung Cancer: Targets and Therapy Pub Date : 2019-03-20 eCollection Date: 2019-01-01 DOI:10.2147/LCTT.S192830
Giuseppe Bronte, Paola Ulivi, Alberto Verlicchi, Paola Cravero, Angelo Delmonte, Lucio Crinò
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引用次数: 55

Abstract

Non-small-cell lung cancer (NSCLC) patients with mutated or rearranged oncogene drivers can be treated with upfront selective inhibitors achieving higher response rates and longer survival than chemotherapy. The RET gene can undergo chromosomal rearrangements in 1%-2% of all NSCLC patients, involving various upstream fusion partners such as KIF5B, CCDC6, NCOA4, and TRIM33. Many multikinase inhibitors are active against rearranged RET. Cabozantinib, vandetanib, sunitinib, lenvatinib, and nintedanib achieved tumor responses in about 30% of these patients in retrospective studies. Prospective phase II trials investigated the activity and toxicity of cabozantinib, vandetanib, sorafenib, and lenvatinib, and did not reach significantly higher response rates. VEGFR and EGFR inhibition represented the main ways of developing off-target toxicity. An intrinsic resistance emerged according to the type of RET fusion partners, as KIF5B-RET fusion is the most resistant. Also acquired mutations in rearranged RET oncogene developed as resistance to these multikinase inhibitors. Interestingly, RET fusions have been found as a resistance mechanism to EGFR-TKIs in EGFR-mutant NSCLC patients. The combination of EGFR and RET inhibition can overcome this resistance. The limitations in terms of activity and tolerability of the various multikinase inhibitors prompted the investigation of new highly selective RET inhibitors, such as RXDX-105, BLU-667, and LOXO-292. Some data emerged about intracranial antitumor activity of BLU-667 and LOXO-292. If these novel drugs will achieve high activity in RET rearranged NSCLC, also these oncogene-addicted tumors can undergo a significant survival improvement.

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靶向ret重排非小细胞肺癌:未来展望
癌基因驱动突变或重排的非小细胞肺癌(NSCLC)患者可以使用前期选择性抑制剂治疗,获得比化疗更高的反应率和更长的生存期。RET基因可在1%-2%的NSCLC患者中发生染色体重排,涉及各种上游融合伙伴,如KIF5B、CCDC6、NCOA4和TRIM33。许多多激酶抑制剂对重排RET有活性。在回顾性研究中,Cabozantinib、vandetanib、舒尼替尼、lenvatinib和nintedanib在约30%的患者中达到肿瘤应答。前瞻性II期试验研究了cabozantinib、vandetanib、sorafenib和lenvatinib的活性和毒性,并没有达到明显更高的应答率。VEGFR和EGFR抑制是脱靶毒性产生的主要途径。根据RET融合伙伴的类型,出现了内在阻力,其中KIF5B-RET融合阻力最大。此外,重排RET癌基因的获得性突变发展为对这些多激酶抑制剂的抗性。有趣的是,在egfr突变的NSCLC患者中,RET融合被发现是对EGFR-TKIs的一种耐药机制。EGFR和RET联合抑制可以克服这种抗性。各种多激酶抑制剂在活性和耐受性方面的局限性促使研究新的高选择性RET抑制剂,如RXDX-105, BLU-667和LOXO-292。一些关于BLU-667和LOXO-292颅内抗肿瘤活性的数据已经出现。如果这些新药能够在RET重排NSCLC中实现高活性,那么这些癌基因依赖的肿瘤也可以显著改善生存。
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来源期刊
CiteScore
8.10
自引率
0.00%
发文量
10
审稿时长
16 weeks
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