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首页> 外文期刊>Lung Cancer: Targets and Therapy >Targeting RET-rearranged non-small-cell lung cancer: future prospects
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Targeting RET-rearranged non-small-cell lung cancer: future prospects

机译：靶向RET重排的非小细胞肺癌：未来前景

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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.
机译：突变或重排致癌基因驱动子的非小细胞肺癌（NSCLC）患者可以用预先选择的抑制剂治疗，与化学疗法相比，它们具有更高的应答率和更长的生存期。 RET基因可在所有NSCLC患者中发生1％–2％的染色体重排，涉及各种上游融合伴侣，例如KIF5B，CCDC6，NCOA4和TRIM33。许多多激酶抑制剂对重排的RET具有活性。在回顾性研究中，卡波扎替尼，凡德他尼，舒尼替尼，兰瓦替尼和nintedanib在这些患者中约有30％实现了肿瘤反应。前瞻性II期临床试验调查了卡博替尼，vandetanib，索拉非尼和lenvatinib的活性和毒性，但未达到明显更高的缓解率。 VEGFR和EGFR抑制是发展脱靶毒性的主要途径。根据RET融合伴侣的类型，出现内在抗性，因为KIF5B-RET融合是最强的抗性。在重排的RET癌基因中也获得了突变，从而对这些多激酶抑制剂产生了抗性。有趣的是，已发现RET融合是EGFR突变型NSCLC患者对EGFR-TKIs的耐药机制。 EGFR和RET抑制的组合可以克服这种耐药性。各种多激酶抑制剂在活性和耐受性方面的局限性促使人们研究新的高选择性RET抑制剂，例如RXDX-105，BLU-667和LOXO-292。有关BLU-667和LOXO-292的颅内抗肿瘤活性的一些数据出现了。如果这些新药将在RET重排的NSCLC中实现高活性，那么这些致癌基因致癌的肿瘤也可以显着改善生存率。

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