Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2019 Nov 14;9(1):16832. doi: 10.1038/s41598-019-53322-y.
Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneous role in ovarian cancer chemotherapy resistance remains poorly elucidated. The aim of this work is to determine the effects of dual IGF-1R/ErbB3 inhibition on ovarian cancer cell signaling, growth, and in vivo efficacy. Assessment of in vitro chemotherapy response across a panel of ovarian cancer cell lines revealed that increased IGF-1R cell surface expression correlates with decreased sensitivity to chemotherapy, and that growth induced by IGF-1R and ErbB3 ligands is blocked by the tetravalent bispecific antibody targeting IGF-1R and ErbB3, istiratumab. In vitro chemotherapy treatment increased ovarian cancer cell line capacity to activate prosurvival PI3K signaling in response to ligand, which could be prevented with istiratumab treatment. Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer.
治疗性靶向受体酪氨酸激酶已被证明对克服几种癌症适应症中的化疗耐药性至关重要，可改善患者的预后。胰岛素样生长因子受体 1 (IGF-1R) 和表皮生长因子受体 3 (ErbB3) 已被认为是两种耐药性的驱动因素，但它们在卵巢癌化疗耐药性中的同时作用仍未得到充分阐明。这项工作的目的是确定双重 IGF-1R/ErbB3 抑制对卵巢癌细胞信号转导、生长和体内疗效的影响。在一系列卵巢癌细胞系中评估体外化疗反应表明，IGF-1R 细胞表面表达增加与化疗敏感性降低相关，IGF-1R 和 ErbB3 配体诱导的生长可被靶向 IGF-1R 和 ErbB3 的四价双特异性抗体 istiratumab 阻断。体外化疗治疗增加了卵巢癌细胞系对配体激活生存 PI3K 信号的能力，而 istiratumab 治疗可预防这种能力。此外，使用卵巢癌异种移植模型的标准治疗化疗的体内疗效也可通过 istiratumab 增强。我们的研究结果表明，IGF-1R 和 ErbB3 在驱动卵巢癌化疗耐药性中起作用。
