Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

中文翻译：

---

RET 的标志和 RET 异常癌症中同时发生的基因组改变

激活转染过程中重排的受体酪氨酸激酶 (RET) 突变和融合是肿瘤发生的有力驱动因素。FDA 最近批准了高效和选择性 RET 抑制剂 selpercatinib 和 pralsetinib，改变了 RET 异常肿瘤的治疗管理。有充分证据表明 RET 信号在某些癌症中的作用。RET 畸变作为融合或突变发生在多种癌症中，但是，存在相当大的表型多样性。有新的数据表明免疫疗法对 RET 改变的癌症缺乏反应。在此，我们回顾了选择性 RET 抑制剂试验的注册数据，并全面探讨了泛癌成人恶性肿瘤中的 RET 改变及其协同改变。这些共同发生的改变可能会定义 RET 抑制的未来，从特定的选择性靶向到定制的联合疗法，因为关于靶向和脱靶获得性耐药机制的数据正在迅速出现。令人着迷的是，据报道，致癌 RET 融合介导了对 EGFR 抑制和 KRASG12C 抑制的耐药性。