Resistance to TRK inhibition mediated by convergent MAPK pathway activation.,Nature Medicine

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Resistance to TRK inhibition mediated by convergent MAPK pathway activation.
Nature Medicine ( IF 58.7 ) Pub Date : 2019-08-12 , DOI: 10.1038/s41591-019-0542-z
Emiliano Cocco _{1,

2} , Alison M Schram _{3,

4} , Amanda Kulick _{5,

6} , Sandra Misale ₅ , Helen H Won ₇ , Rona Yaeger _{3,

5} , Pedram Razavi _{1,

3} , Ryan Ptashkin ₂ , Jaclyn F Hechtman ₂ , Eneda Toska ₁ , James Cownie ₁ , Romel Somwar _{1,

2} , Sophie Shifman _{1,

2} , Marissa Mattar _{5,

6} , S Duygu Selçuklu ₈ , Aliaksandra Samoila ₈ , Sean Guzman _{5,

6} , Brian B Tuch ₉ , Kevin Ebata ₉ , Elisa de Stanchina _{5,

7} , Rebecca J Nagy ₁₀ , Richard B Lanman ₁₀ , Brian Houck-Loomis ₇ , Juber A Patel ₇ , Michael F Berger _{1,

2,

7} , Marc Ladanyi _{1,

2} , David M Hyman _{3,

4} , Alexander Drilon _{3,

4} , Maurizio Scaltriti _{1,

2}

Affiliation

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. 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 inhibitors9-11. 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 MAPK pathway-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.

中文翻译：

会聚 MAPK 通路激活介导的对 TRK 抑制的抗性。

TRK 融合存在于多种癌症类型中，导致致癌成瘾，并强烈预测 TRK 抑制的肿瘤不可知疗效1-8。随着第一个选择性 TRK 抑制剂 larotrectinib 最近获得批准，用于任何 TRK 融合阳性成人或儿童实体瘤的患者，以确定初始反应后治疗失败的机制已成为直接的治疗相关性。到目前为止，唯一已知的耐药机制是获得靶向 TRK 激酶结构域突变，这会干扰药物结合，并可能通过第二代 TRK 抑制剂9-11 解决。在这里，我们报告了用 TRK 抑制剂治疗的患者和患者衍生模型中的脱靶耐药性，这种耐药性由基因组改变介导，这些改变会聚合激活丝裂原活化蛋白激酶 (MAPK) 途径。MAPK 通路定向靶向治疗，单独给药或与 TRK 抑制联合给药，重新建立了疾病控制。实验模型进一步表明，TRK 和 MEK 的前期双重抑制可能会延迟易于获得 MAPK 通路激活改变的基因组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影响。实验模型进一步表明，TRK 和 MEK 的前期双重抑制可能会延迟易于获得 MAPK 通路激活改变的基因组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影响。实验模型进一步表明，TRK 和 MEK 的前期双重抑制可能会延迟易于获得 MAPK 通路激活改变的基因组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影响。

更新日期：2019-08-12

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