Notarangelo Tiziana, Sisinni Lorenza, Condelli Valentina, Landriscina Matteo
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Via Padre Pio, 1, Rionero in Vulture, 85028 Italy.
Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, Foggia, 71100 Italy.
Cancer Cell Int. 2017 Oct 4;17:86. doi: 10.1186/s12935-017-0457-z. eCollection 2017.
BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells.
Cell proliferation, cell cycle distribution, induction of apoptosis and EGFR and AKT signaling were evaluated in thyroid carcinoma cell lines bearing the BRAF V600E mutation in response to PLX4032.
A partial and transient cytostatic response to PLX4032 was observed in thyroid carcinoma cell lines bearing the BRAF V600E mutation, with lack of full inhibition of ERK pathway. Interestingly, the exposure of thyroid carcinoma cells to PLX4032 resulted in a rapid feedback activation of EGFR signaling with parallel activation of AKT phosphorylation. Consistently, the dual inhibition of EGFR and BRAF, through combination therapy with PLX4032 and gefitinib, resulted in prevention of EGFR phosphorylation and sustained inhibition of ERK and AKT signaling and cell proliferation. Of note, the combined treatment with gefitinib and vemurafenib or the exposure of EGFR-silenced thyroid carcinoma cells to vemurafenib induced synthetic lethality compared to single agents.
These data suggest that the dual EGFR and BRAF blockade represents a strategy to by-pass resistance to BRAF inhibitors in thyroid carcinoma cells.
BRAF抑制剂是BRAF突变型黑色素瘤有效的抗癌药物。相比之下，关于甲状腺癌对BRAF抑制敏感性的证据相互矛盾，有人提出BRAF V600E甲状腺癌细胞由于平行信号通路的激活而对BRAF抑制剂不太敏感。本研究评估了以下假设：EGFR信号的反馈激活抵消了维莫非尼（PLX4032）在BRAF V600E甲状腺癌细胞中的细胞生长抑制活性。
在携带BRAF V600E突变的甲状腺癌细胞系中，评估对PLX4032的细胞增殖、细胞周期分布、凋亡诱导以及EGFR和AKT信号传导。
在携带BRAF V600E突变的甲状腺癌细胞系中观察到对PLX4032的部分和短暂的细胞生长抑制反应，ERK通路缺乏完全抑制。有趣的是，甲状腺癌细胞暴露于PLX4032导致EGFR信号的快速反馈激活以及AKT磷酸化的平行激活。一致地，通过PLX4032与吉非替尼联合治疗对EGFR和BRAF的双重抑制，导致EGFR磷酸化的预防以及ERK和AKT信号传导和细胞增殖的持续抑制。值得注意的是，与单一药物相比，吉非替尼和维莫非尼联合治疗或EGFR沉默的甲状腺癌细胞暴露于维莫非尼诱导了合成致死性
这些数据表明EGFR和BRAF双重阻断是一种绕过甲状腺癌细胞对BRAF抑制剂耐药的策略。
