Maiello Monica Rosaria, D'Alessio Amelia, Bevilacqua Simona, Gallo Marianna, Normanno Nicola, De Luca Antonella
Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
J Cell Biochem. 2015 Dec;116(12):2778-85. doi: 10.1002/jcb.25220.
Although evidence suggests that the RAF/MEK/ERK pathway plays an important role in triple negative breast cancer (TNBC), resistance to MEK inhibitors has been observed in TNBC cells. Different mechanisms have been hypothesized to be involved in this phenomenon, including receptor tyrosine kinase-dependent activation of the PI3K/AKT pathway. In this study, we analyzed the effects of the MEK1/2 inhibitor selumetinib in combination with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in a panel of TNBC cell lines that showed different levels of sensitivity to single-agent selumetinib: SUM-149 and MDA-MB-231 cells resulted to be sensitive, whereas SUM-159, MDA-MB-468 and HCC70 cells were relatively resistant to the drug. Treatment of TNBC cells with selumetinib produced an increase of the phosphorylation of the EGFR both in selumetinib-sensitive SUM-149, MDA-MB-231 and in selumetinib-resistant MDA-MB-468 TNBC cells. The combination of selumetinib and gefitinib resulted in a synergistic growth inhibitory effect in all the TNBC cell lines, although the IC50 was not reached in SUM-159 and MDA-MB-468 cells. This effect was associated with an almost complete suppression of ERK1/2 activation and a reduction of selumetinib-induced AKT phosphorylation. In addition, in selumetinib-sensitive TNBC cells the combination of selumetinib and gefitinib induced a significant G0/G1 cell cycle arrest and apoptosis. Taken together, our data demonstrated that blockade of the EGFR might efficiently increase the antitumor activity of selumetinib in a subgroup of TNBC and that this phenomenon might be related to the effects of such combination on both ERK1/2 and AKT activation.
尽管有证据表明RAF/MEK/ERK通路在三阴性乳腺癌（TNBC）中起重要作用，但在TNBC细胞中已观察到对MEK抑制剂的耐药性。已推测不同机制参与此现象，包括受体酪氨酸激酶依赖性激活PI3K/AKT通路。在本研究中，我们分析了MEK1/2抑制剂司美替尼与表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼联合使用对一组对单药司美替尼表现出不同敏感性的TNBC细胞系的影响：SUM-149和MDA-MB-231细胞对司美替尼敏感，而SUM-159、MDA-MB-468和HCC70细胞对该药物相对耐药。用司美替尼处理TNBC细胞导致司美替尼敏感的SUM-149、MDA-MB-231以及司美替尼耐药的MDA-MB-468 TNBC细胞中EGFR磷酸化增加。司美替尼和吉非替尼联合使用在所有TNBC细胞系中均产生协同生长抑制作用，尽管在SUM-159和MDA-MB-468细胞中未达到IC50。这种作用与ERK1/2激活的几乎完全抑制以及司美替尼诱导的AKT磷酸化的减少有关。此外，在司美替尼敏感的TNBC细胞中，司美替尼和吉非替尼联合使用诱导了显著的G0/G1细胞周期停滞和凋亡。综上所述，我们的数据表明，阻断EGFR可能有效增加司美替尼在一部分TNBC中的抗肿瘤活性，并且这种现象可能与该联合用药对ERK1/2和AKT激活的影响有关。
