Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa, Italy.
Crit Rev Oncol Hematol. 2021 Apr;160:103234. doi: 10.1016/j.critrevonc.2021.103234. Epub 2021 Jan 23.
MET receptor has emerged as a druggable target across several human cancers. Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping. In this review, we critically examine the current evidence on how HGF/MET combination therapies may take advantage of synergistic effects, overcome primary or acquired drug resistance, target tumor microenvironment, modulate drug metabolism or tackle pharmacokinetic issues. Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (including EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.
MET 受体已成为多种人类癌症的可用药靶点。针对 MET 和其配体肝细胞生长因子（HGF）的药物，包括小分子药物如克唑替尼、替沃扎尼布和卡博替尼，以及抗体药物如雷莫芦单抗和奥马珠单抗，已在不同肿瘤中证明了其价值。最近，卡马替尼被批准用于治疗携带 MET 外显子 14 跳跃的转移性肺癌。在这篇综述中，我们批判性地评估了 HGF/MET 联合治疗如何利用协同作用、克服原发性或获得性耐药、靶向肿瘤微环境、调节药物代谢或解决药代动力学问题的现有证据。我们还研究了 HGF/MET 靶向药物与传统化疗药物或分子靶向治疗（包括 EGFR、VEGFR、HER2、RAF/MEK 和 PI3K/Akt 靶向药物）联合应用的临床前和临床研究，以及生物标志物的价值。深入了解成功的药物联合治疗的分子机制对于为癌症患者找到最佳的个体化治疗方案至关重要。
