Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Sci Rep. 2020 Feb 17;10(1):2735. doi: 10.1038/s41598-020-59466-6.
Resistance to cancer therapy is a challenge because of innate tumor heterogeneity and constant tumor evolution. Since the pathway of resistance cannot be predicted, combination therapies may address this progression. We discovered that in addition to IGF1 and IGF2, IGFBP-3 binds bFGF, HGF, neuregulin, and PDGF AB with nanomolar affinity. Because growth factors drive resistance, simultaneous inhibition of multiple growth factor pathways may improve the efficacy of precision therapy. Growth factor sequestration by IGFBP-3-Fc enhances the activity of EGFR inhibitors by decreasing cell survival and inhibiting bFGF, HGF, and IGF1 growth factor rescue and also potentiates the activity of other cancer drugs. Inhibition of tumor growth in vivo with adjuvant IGFBP-3-Fc with erlotinib versus erlotinib after treatment cessation supports that the combination reduces cell survival. Inhibition of multiple growth factor pathways may postpone resistance and extend progression-free survival in many cancer indications.
由于肿瘤固有异质性和不断进化，癌症治疗的耐药性是一个挑战。由于无法预测耐药途径，联合治疗可能会解决这一进展。我们发现，除了 IGF1 和 IGF2 之外，IGFBP-3 还以纳摩尔亲和力结合 bFGF、HGF、神经调节素和 PDGF AB。由于生长因子会导致耐药性，因此同时抑制多种生长因子通路可能会提高精准治疗的疗效。IGFBP-3-Fc 对生长因子的隔离通过降低细胞存活率并抑制 bFGF、HGF 和 IGF1 生长因子的挽救作用，增强了 EGFR 抑制剂的活性，同时也增强了其他癌症药物的活性。在治疗停止后，用辅助 IGFBP-3-Fc 联合厄洛替尼与单用厄洛替尼抑制体内肿瘤生长的实验支持了这种联合用药减少细胞存活的作用。抑制多种生长因子通路可能会推迟耐药性并延长多种癌症适应症的无进展生存期。
