美国纪念斯隆凯瑟琳癌症研究中心Maurizio Scaltriti、Alexander Drilon小组领导的联合研究团队近日取得一项新成果。他们研究了通过趋同MAPK途径激活介导对TRK抑制的抗性。该2019年9月发表在《自然—医学》上。

TRK融合体存在于多种癌症类型中，可导致致癌成瘾，TRK抑制能够预测肿瘤诊断。最近批准了第一个选择性TRK抑制剂，larotrectinib，可用于任何TRK-融合阳性成人或小儿实体瘤的患者。到目前为止，唯一已知的抗性机制是获得靶向TRK激酶结构域突变，这种突变会干扰药物结合，并且可能通过第二代TRK抑制剂来解决。

研究组使用TRK抑制剂治疗的患者和患者衍生的模型中出现的靶外耐药，这种耐药由基因组改变介导，其改变会聚以激活丝裂原活化蛋白激酶（MAPK）途径。MAPK通路定向靶向治疗，单独施用或与TRK抑制组合施用，重建疾病控制。实验模型进一步表明，TRK和MEK的前期双重抑制推迟了易于基因组获得MAPK途径激活改变的癌症类型的进展时间。总的来说，这些数据表明，一部分患者将发展出对TRK抑制产生耐药性的脱靶机制，这对临床管理和未来的临床试验设计具有潜在的意义。用选择性TRK抑制剂（包括新批准的larotrectinib）治疗的一部分患者发展由基因组获得MAPK途径激活改变介导的脱靶抗性，并可能受益于联合靶向治疗。

附：英文原文

Title: Resistance to TRK inhibition mediated by convergent MAPK pathway activation

Author: Emiliano Cocco, Alison M. Schram, Amanda Kulick, Sandra Misale, Helen H. Won, Rona Yaeger, Pedram Razavi, Ryan Ptashkin, Jaclyn F. Hechtman, Eneda Toska, James Cownie, Romel Somwar, Sophie Shifman, Marissa Mattar, S. Duygu Seluklu, Aliaksandra Samoila, Sean Guzman, Brian B. Tuch, Kevin Ebata, Elisa de Stanchina, Rebecca J. Nagy, Richard B. Lanman, Brian Houck-Loomis, Juber A. Patel, Michael F. Berger, Marc Ladanyi, David M. Hyman, Alexander Drilon, Maurizio Scaltriti

Issue&Volume: Volume 25 Issue 9

Abstract: TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition18. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors911. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPKpathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design. A subset of patients treated with selective TRK inhibitors (including the newly approved larotrectinib) develop off-target resistance mediated by genomic acquisition of MAPK pathway-activating alterations, and may benefit from combined targeted therapy.

DOI: 10.1038/s41591-019-0542-z

Source:https://www.nature.com/articles/s41591-019-0542-z