Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma.
Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma.
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DOI：
10.1158/1535-7163.mct-16-0352
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发表时间：
2017-04
影响因子：
5.7
通讯作者：
Yang ES
中科院分区：
文献类型：
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作者：
Zeng L;Beggs RR;Cooper TS;Weaver AN;Yang ES
EGFR抑制和放射治疗是DNA损伤的有效诱因。检查点激酶1和2(Chk1/2)是DNA损伤反应的关键调节因子，控制细胞周期检查点，可能允许从与治疗相关的基因组应激中恢复。我们推测，用prexasertib抑制Chk1/2(CHKi)可能会增强EGFR抑制加放疗对头颈部鳞状细胞癌(HNSCC)的细胞毒作用。在这项研究中，我们发现，在接受和不接受放射治疗的情况下，在EGFR抑制剂西妥昔单抗中加入CHKi显著降低了HPV阳性和HPV阴性HNSCC细胞系的细胞增殖和存活率。细胞增殖减少的同时伴随着检查点激活的减少，导致S期蓄积，持续的DNA损伤，caspase裂解和细胞凋亡增加。重要的是，在接受CHKI、西妥昔单抗和放射治疗三联治疗的HPV阳性和HPV阴性的异种细胞系中，体内观察到显著的肿瘤生长延迟，而没有伴随着小鼠体重评估的毒性增加。综上所述，CHKI联合西妥昔单抗加放射治疗在体内外对HNSCCs均显示出显著的抗肿瘤作用，提示该联合治疗可提高临床效益。一项针对头颈癌患者的临床试验目前正在进行中(NCT02555644)。
EGFR inhibition and radiotherapy are potent inducers of DNA damage. Checkpoint kinases 1 and 2 (Chk1/2) are critical regulators of the DNA-damage response, controlling cell-cycle checkpoints that may permit recovery from therapy-associated genomic stress. We hypothesized that Chk1/2 inhibition (CHKi) with prexasertib may enhance cytotoxicity from EGFR inhibition plus radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study, we found that the addition of CHKi to the EGFR inhibitor cetuximab with and without radiotherapy significantly decreased cell proliferation and survival fraction in human papillomavirus virus (HPV)-positive and HPV-negative HNSCC cell lines. Reduced proliferation was accompanied by decreased checkpoint activation, induced S-phase accumulation, persistent DNA damage, and increased caspase cleavage and apoptosis. Importantly, a significant tumor growth delay was observed in vivo in both HPV-positive and HPV-negative cell line xenografts receiving triple combination therapy with CHKi, cetuximab, and radiotherapy without a concomitant increase in toxicity as assessed by mouse body weight. Taken together, the combination of CHKi with cetuximab plus irradiation displayed significant antitumor effects in HNSCCs both in vitro and in vivo, suggesting that this combination therapy may increase clinical benefit. A clinical trial to test this treatment for patients with head and neck cancer is currently ongoing (NCT02555644).