Fancelli Sara, Caliman Enrico, Mazzoni Francesca, Brugia Marco, Castiglione Francesca, Voltolini Luca, Pillozzi Serena, Antonuzzo Lorenzo
Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Cancers (Basel). 2021 Mar 4;13(5):1091. doi: 10.3390/cancers13051091.
The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.
强效、RET 选择性酪氨酸激酶抑制剂（TKIs）普拉替尼和塞普替尼对 RET V804L/M 守门人突变有效，然而，已发现导致 RET G810 溶剂前沿残基产生耐药性的适应性突变，这表明需要开发下一代 RET 特异性 TKIs。此外，正如在 EGFR 和 ALK 驱动的非小细胞肺癌中所见，KRAS 和 MET 共发生扩增的增加可能代表其他直接抑制逃逸机制。在本综述中，我们总结了关于 RET 融合的实际知识，重点关注那些参与非小细胞肺癌的融合、已批准的 RET 抑制药物的主要临床试验结果，特别关注选择性 TKIs 的最新发表结果，最后是关于耐药机制的临床前证据以及对近期可行的假设性和可行性药物组合及策略的建议。
