Trouvilliez Sarah, Lagadec Chann, Toillon Robert-Alain
Univ. Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, OncoLille Institute, Bvd. du Professeur Jules Leclercq, F-59000 Lille, France.
GdR2082 APPICOM-«Approche Intégrative Pour Une Compréhension Multi-Échelles de la Fonction des Protéines Membranaires», 75016 Paris, France.
Cancers (Basel). 2023 Mar 23;15(7):1943. doi: 10.3390/cancers15071943.
Larotrectinib and Entrectinib are specific pan-Trk tyrosine kinase inhibitors (TKIs) approved by the Food and Drug Administration (FDA) in 2018 for cancers with an NTRK fusion. Despite initial enthusiasm for these compounds, the French agency (HAS) recently reported their lack of efficacy. In addition, primary and secondary resistance to these TKIs has been observed in the absence of other mutations in cancers with an NTRK fusion. Furthermore, when TrkA is overexpressed, it promotes ligand-independent activation, bypassing the TKI. All of these clinical and experimental observations show that genetics does not explain all therapeutic failures. It is therefore necessary to explore new hypotheses to explain these failures. This review summarizes the current status of therapeutic strategies with TrkA inhibitors, focusing on the mechanisms potentially involved in these failures and more specifically on the role of TrkA.
拉罗替尼和恩曲替尼是特定的泛Trk酪氨酸激酶抑制剂（TKIs），于2018年被美国食品药品监督管理局（FDA）批准用于治疗具有NTRK融合的癌症。尽管最初对这些化合物充满热情，但法国药品安全局（HAS）最近报告称它们缺乏疗效。此外，在具有NTRK融合的癌症中，在没有其他突变的情况下，已观察到对这些TKIs的原发性和继发性耐药性。此外，当TrkA过度表达时，它会促进非配体依赖性激活，从而绕过TKI。所有这些临床和实验观察结果表明，遗传学并不能解释所有的治疗失败。因此，有必要探索新的假说来解释这些失败。本综述总结了TrkA抑制剂治疗策略的现状，重点关注这些失败可能涉及的机制，更具体地关注TrkA的作用。
