Bosch-Vilaró Albert, Jacobs Bart, Pomella Valentina, Abbasi Asbagh Layka, Kirkland Richard, Michel Joe, Singh Sharat, Liu Xinjun, Kim Phillip, Weitsman Gregory, Barber Paul R, Vojnovic Borivoj, Ng Tony, Tejpar Sabine
Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
Prometheus Laboratories, San Diego, CA, USA.
Oncotarget. 2017 Jan 17;8(3):4277-4288. doi: 10.18632/oncotarget.13834.
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment. Interestingly, lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, blocked the increase of cetuximab-induced HER3 phosphorylation. Additionally, we showed that upon HER3 knockdown, cetuximab combined with lapatinib was able to decrease cell viability compared to HER3 expressing cells. These results suggest the existence of a cetuximab-induced feedback HER3 activation that could potentially result in reduced cetuximab efficacy in colorectal cancer patients. Taken together, we provide evidence of the limited effectiveness of cetuximab monotherapy compared to rational combinations.
表皮生长因子受体（EGFR）抑制剂西妥昔单抗已被批准用于治疗结直肠癌。然而，包括代偿性反馈回路在内的固有和获得性耐药机制限制了其疗效。尽管如此，这些反馈回路的出现至今仍 largely 未被探索。在此，我们展示了在结肠癌细胞中，西妥昔单抗治疗后HER3的反馈上调和HER3磷酸化的诱导。我们还表明，这种上调至少部分是通过AKT抑制发生的。与此同时，我们观察到西妥昔单抗治疗后HER2:HER3二聚化增加。有趣的是，拉帕替尼，一种双重EGFR和HER2酪氨酸激酶抑制剂，阻断了西妥昔单抗诱导的HER3磷酸化的增加。此外，我们表明，与表达HER3的细胞相比，在HER3敲低后，西妥昔单抗与拉帕替尼联合能够降低细胞活力。这些结果表明存在西妥昔单抗诱导的反馈性HER3激活，这可能导致西妥昔单抗在结直肠癌患者中的疗效降低。综上所述，我们提供了证据表明与合理联合用药相比，西妥昔单抗单药治疗的有效性有限。
