Kim Jung Eun, Kim Youjin, Li Gary, Kim Seung Tae, Kim Kyung, Park Se Hoon, Park Joon Oh, Park Young Suk, Lim Ho Yeong, Lee Hyuk, Sohn Tae Sung, Kim Kyoung-Mee, Kang Won Ki, Lee Jeeyun
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Ignyta, Inc., San Diego, CA, USA.
Oncotarget. 2017 Nov 11;8(62):105727-105734. doi: 10.18632/oncotarget.22394. eCollection 2017 Dec 1.
RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment. We also investigated the effect of RXDX-106 in patient-derived cell lines to mimic the condition. The prevalence of MerTK protein overexpression was evaluated in 229 cancer tissue specimens. We have found that MerTK inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling. In addition, MerTK phosphorylation, not total MerTK expression, is likely more predictive of therapeutic success. p-MerTK protein overexpression by IHC was found in 18% (17/87) of GC patients. Lastly, RXDX-106 inhibited cell proliferation in MerTK activated gastric cancer cell line. These findings provide further evidence of oncogenic roles for MerTK in GC, and demonstrate the importance of kinase activity for MerTK tumorigeneicity and validate RXDX-106, a novel MerTK inhibitor, as a potential therapeutic agent for treatment of GC.
RXDX-106是一种强效且具有选择性的II型伪不可逆（解离速率慢）的TYRO3、AXL、MER和c-MET抑制剂。MER酪氨酸激酶（MerTK）在包括胃癌（GC）在内的多种恶性肿瘤中表达。多条证据支持了MerTK的致癌潜力。首先，我们检测了10种胃癌细胞系中MerTK蛋白的过表达和MerTk的磷酸化情况。接下来，我们评估了RXDX-106处理后下游信号分子（包括磷酸化ERK和磷酸化AKT）的变化。我们还研究了RXDX-106在患者来源的细胞系中的作用，以模拟实际情况。在229个癌症组织标本中评估了MerTK蛋白过表达的发生率。我们发现MerTK抑制剂处理导致细胞生长和下游信号受到显著抑制。此外，MerTK的磷酸化而非总的MerTK表达可能更能预测治疗效果。通过免疫组化发现，18%（17/87）的胃癌患者存在p-MerTK蛋白过表达。最后，RXDX-106抑制了MerTK激活的胃癌细胞系中的细胞增殖。这些发现为MerTK在胃癌中的致癌作用提供了进一步证据，证明了激酶活性对MerTK致瘤性的重要性，并验证了新型MerTK抑制剂RXDX-106作为治疗胃癌潜在治疗药物的有效性。
