Gaborit Nadège, Abdul-Hai Ali, Mancini Maicol, Lindzen Moshit, Lavi Sara, Leitner Orith, Mounier Lucile, Chentouf Myriam, Dunoyer Sai, Ghosh Manjusha, Larbouret Christel, Chardès Thierry, Bazin Hervé, Pèlegrin André, Sela Michael, Yarden Yosef
Departments of Biological Regulation.
Departments of Biological Regulation, Department of Internal Medicine, Kaplan Medical Center, Rehovot 76100, Israel.
Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):839-44. doi: 10.1073/pnas.1423645112. Epub 2015 Jan 6.
The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.
人类表皮生长因子受体（HER/EGFR）家族的受体酪氨酸激酶是癌症治疗的关键靶点。具体而言，EGFR和HER2因其在肿瘤中的基因畸变而一直是反复靶向的对象。由于在肿瘤中表达相对较低且激酶活性受损，HER3的治疗潜力长期以来一直被低估。然而，除了作为EGFR和HER2的二聚化伙伴外，HER3在肿瘤细胞获得抗癌药物耐药性的能力中起着关键作用。在本研究中，我们制备了几种针对HER3的单克隆抗体。通过比较它们降解HER3、减少下游信号传导、抑制培养细胞生长以及募集免疫效应细胞的能力，选择了一种抗体，该抗体后来成为在动物体内生长为肿瘤的胰腺癌细胞的最有效抑制剂。我们的数据预测，能够阻断自分泌和基质-肿瘤相互作用的抗HER3抗体可能会强烈抑制肿瘤生长，这类似于目前常规用于治疗结直肠癌患者的抗EGFR抗体的作用机制。
