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Has PD-1 MET Its Match in Hepatocellular Carcinoma?
Joseph W. Franses
Massachusetts General Hospital Cancer Center and Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts
Andrew X. Zhu∗,'Correspondence information about the author Andrew X. ZhuEmail the author Andrew X. Zhu
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
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DOI: https://doi.org/10.1053/j.gastro.2019.03.029 |
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See “MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1,” by Li H, Li C-W, Li X, et al, on page 1849.
Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the fourth leading cause of death worldwide.1 Until recently, treatment options for advanced disease have been limited. Sorafenib—a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor (VEGFR), platelet-derived growth factor, and RAF—was initially approved in 2008,2 and this drug had been the only first-line option for systemic therapy of advanced disease until the noninferiority of lenvatinib, a VEGFR/RET/fibroblast growth factor receptor TKI, was demonstrated a decade later.3 Second-line treatment options have emerged over the past few years. These include antiangiogenic TKIs such as regorafenib4 and cabozantinib,5 the anti-VEGFR2-blocking antibody ramucirumab for patients with elevated alpha-fetoprotein,6 and the anti-PD1 immune checkpoint inhibitors nivolumab7 and pembrolizumab.8 In addition to inhibiting VEGFR1-3, cabozantinib is an inhibitor of MET, a target that is up-regulated in preclinical models after treatment with sorafenib.9 Unfortunately, the oral putative MET inhibitor tivantinib failed in a phase III randomized trial to prolong median survival in HCC patients whose disease harbored high baseline MET expression (as assessed by tissue immunohistochemistry) after progression on sorafenib.10 In this issue of Gastroenterology, Li et al11 demonstrate with multiple preclinical HCC models that PD-L1 protein is stabilized in response to the MET inhibitors tivantinib and capmatinib. This finding helps to explain the lack of clinical impact of MET inhibitors as monotherapy and provides a rationale for combining MET TKIs with immune checkpoint inhibitors in HCC.
In this article, the authors unexpectedly observed a differential in vivo efficacy of MET inhibitors when murine HCC cells were implanted into immunocompromised versus immunocompetent hosts, with efficacy seen in the former but not the latter. This difference was correlated with the up-regulation of PD-L1 protein within the tumor cells. They then found that short hairpin RNA-mediated knockdown of MET within HCC cells increased PD-L1 protein expression without changing its gene expression levels. The authors showed that MET inhibition—via TKI treatment or short hairpin RNA-mediated knockdown—decreased the ability of MET to phosphorylate GSK3β at residue Y56, thereby allowing increased access to GSK3β by the TRAF6 ubiquitin ligase and proteasomal degradation of GSK3β. This resulted in higher expression of PD-L1, which would otherwise be degraded by GSK3β. Because MET inhibition caused increased PD-L1 expression in their models, the authors predicted that combining a MET inhibitor with immune checkpoint inhibitors disrupting PD-1/PD-L1 signaling would lead to synergistic antitumor effects (Figure 1). They found in multiple mouse models that such combination therapy indeed led to increased antitumor efficacy and prolonged survival, without causing worse toxicity, when compared with monotherapy. Finally, the authors demonstrated a correlation between several of the key signaling molecules in resected treatment-naive human HCC specimens (high MET expression, high phospho-GSK3β Y56, low PD-L1, low granzyme) in human tumor microarrays. |
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发表于 2019-4-18 20:13