Molecular characterization of oncogenic mutations within genes in the MAPK and PI3K/AKT/mTOR pathways has led to the rational development of targeted therapies. Combining BRAF and MEK inhibitors to target two steps in the MAPK pathway (vertical inhibition) is now standard of care in advanced-stage melanoma harboring BRAF V600 mutation. Encouraging results have been seen in several tumor types with the same mutation, including BRAF V600–mutant non–small cell lung cancer. Yet similar results in other tumors, such as colorectal cancer, have not been observed, highlighting the unique nature of different tumors. Furthermore, considerable cross talk occurs between signaling pathways, and cancer cells usually harbor multiple aberrations and/or develop compensatory mechanisms that drive resistance. Therefore, it is logical to target multiple pathways simultaneously (horizontal inhibition) by combining selective inhibitors or engineering multitargeted agents. Yet horizontal inhibition has proven to be a significant challenge, primarily due to dose-limiting toxicities. This review focuses on ongoing or completed clinical trials with combination targeted therapies for solid tumors and highlights the successes and ongoing challenges. Novel strategies to overcome these obstacles include new delivery technologies, combinations with emerging agents, and treatment schedule optimization. Mol Cancer Ther; 17(1); 3–16. ©2017 AACR.

中文翻译：

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针对实体瘤中 MAP 激酶通路的联合治疗策略的合理方法

MAPK 和 PI3K/AKT/mTOR 通路中基因内致癌突变的分子特征导致靶向治疗的合理发展。结合 BRAF 和 MEK 抑制剂以靶向 MAPK 途径中的两个步骤（垂直抑制）现在是携带 BRAF V600 突变的晚期黑色素瘤的标准治疗方法。在具有相同突变的几种肿瘤类型中已经看到了令人鼓舞的结果，包括 BRAF V600 突变型非小细胞肺癌。然而，尚未在其他肿瘤（如结直肠癌）中观察到类似的结果，这突显了不同肿瘤的独特性。此外，信号通路之间会发生相当多的串扰，癌细胞通常具有多种畸变和/或产生驱动抵抗的补偿机制。所以，通过组合选择性抑制剂或工程化多靶点药物同时靶向多个途径（水平抑制）是合乎逻辑的。然而，水平抑制已被证明是一项重大挑战，主要是由于剂量限制性毒性。本综述重点关注正在进行或已完成的针对实体瘤的联合靶向治疗的临床试验，并强调了成功和持续的挑战。克服这些障碍的新策略包括新的递送技术、与新兴药物的组合以及治疗计划优化。摩尔癌症治疗; 17(1); 3-16。©2017 AACR。本综述重点关注正在进行或已完成的针对实体瘤的联合靶向治疗的临床试验，并强调了成功和持续的挑战。克服这些障碍的新策略包括新的递送技术、与新兴药物的组合以及治疗计划优化。摩尔癌症治疗; 17(1); 3-16。©2017 AACR。本综述重点关注正在进行或已完成的针对实体瘤的联合靶向治疗的临床试验，并强调了成功和持续的挑战。克服这些障碍的新策略包括新的递送技术、与新兴药物的组合以及治疗计划优化。摩尔癌症治疗; 17(1); 3-16。©2017 AACR。