Klinghammer Konrad, Politz Oliver, Eder Theresa, Otto Raik, Raguse Jan-Dirk, Albers Andreas, Kaufmann Andreas, Tinhofer Ingeborg, Hoffmann Jens, Keller Ulrich, Keilholz Ulrich
Department of Hematology and Medical Oncology, Charité, Berlin, Germany.
Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany.
Oncotarget. 2020 Oct 13;11(41):3688-3697. doi: 10.18632/oncotarget.27763.
Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.
尽管最近取得了进展，但头颈部鳞状细胞癌（HNSCC）的治疗仍然是一个未得到满足的医疗需求很高的领域。HNSCC常与PI3K通路的扩增或突变变化相关，这使得PI3K成为一个有吸引力的靶点，尤其是在西妥昔单抗耐药的肿瘤中。在此，我们使用一个小鼠临床试验设置，对33个具有已知HPV和PI3K突变状态且有西妥昔单抗敏感性可用数据的患者来源异种移植（PDX）模型，探索了选择性泛I类PI3K抑制剂库潘尼西在单药治疗以及与西妥昔单抗联合治疗时对PI3Kα和δ具有主要活性的抗肿瘤活性。单独使用库潘尼西治疗产生了中度抗肿瘤活性，33个PDX模型中有12个显示肿瘤稳定或缩小。在大多数模型（21/33）中，库潘尼西与西妥昔单抗联合治疗优于单独的任何一种单药治疗，并且在西妥昔单抗耐药的肿瘤（14/16）中效果尤为显著。虽然未观察到PI3K突变状态与对西妥昔单抗或库潘尼西的反应之间存在相关性，但通过基因表达谱评估的PI3K信号活性增加与对库潘尼西的反应呈正相关。总之，这些数据支持对头颈部鳞状细胞癌中PI3K抑制进行进一步研究，并表明与PI3K信号相关的基因表达模式作为预测治疗反应的潜在生物标志物。
