Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer.
Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer.
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DOI：
10.1016/j.neo.2014.06.004
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发表时间：
2014-07
期刊：
影响因子：
4.8
通讯作者：
Bauer, Todd W.
中科院分区：
文献类型：
--
作者：
Lindberg, James M.;Newhook, Timothy E.;Adair, Sara J.;Walters, Dustin M.;Kim, Alison J.;Stelow, Edward B.;Parsons, J. Thomas;Bauer, Todd W.
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变和表皮生长因子受体（EGFR）家族信号是胰腺导管腺癌（PDAC）发生的驱动因素。先前的研究表明，与丝裂原活化蛋白激酶-细胞外信号调节激酶（ERK）激酶1/2 （MEK1/2）抑制剂曲美替尼和双EGFR/人表皮生长因子受体2 （HER2）抑制剂拉帕替尼联合治疗PDAC异种移植物比单独治疗更有效。在这项研究中，我们使用治疗性抗体，帕尼珠单抗（特异性EGFR）和曲妥珠单抗（特异性HER2），来探索EGFR和HER2信号在患者来源的异种移植（PDX）肿瘤增殖中的作用。我们发现，双重抗egfr和抗her2治疗显著增强了MEK1/2抑制剂trametinib在三种不同的PDX肿瘤中的生长抑制作用。虽然在接受曲美替尼和双抗体治疗的KRAS突变异种移植物组（肿瘤366和608）中观察到显著的生长抑制，但在KRAS野生型异种移植物组（肿瘤738）中观察到肿瘤消退。与曲美替尼加拉帕替尼相比，双抗体治疗联合曲美替尼在抑制肿瘤生长方面同样或更有效，且明显毒性更低。总之，这些研究进一步支持了EGFR和HER2在胰腺癌增殖中的作用，并强调了对kras -快速加速纤维肉瘤激酶(RAF) -MEK-ERK和EGFR-HER2途径进行治疗干预的重要性，以使患者获得最大的治疗效果。
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and epidermal growth factor receptor (EGFR) family signaling are drivers of tumorigenesis in pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated that combinatorial treatment of PDAC xenografts with the mitogen-activated protein kinase–extracellular-signal-regulated kinase (ERK) kinase1/2 (MEK1/2) inhibitor trametinib and the dual EGFR/human epidermal growth factor receptor 2 (HER2) inhibitor lapatinib provided more effective inhibition than either treatment alone. In this study, we have used the therapeutic antibodies, panitumumab (specific for EGFR) and trastuzumab (specific for HER2), to probe the role of EGFR and HER2 signaling in the proliferation of patient-derived xenograft (PDX) tumors. We show that dual anti-EGFR and anti-HER2 therapy significantly augmented the growth inhibitory effects of the MEK1/2 inhibitor trametinib in three different PDX tumors. While significant growth inhibition was observed in both KRAS mutant xenograft groups receiving trametinib and dual antibody therapy (tumors 366 and 608), tumor regression was observed in the KRAS wild-type xenografts (tumor 738) treated in the same manner. Dual antibody therapy in conjunction with trametinib was equally or more effective at inhibiting tumor growth and with lower apparent toxicity than trametinib plus lapatinib. Together, these studies provide further support for a role for EGFR and HER2 in pancreatic cancer proliferation and underscore the importance of therapeutic intervention in both the KRAS–rapidly accelerated fibrosarcoma kinase (RAF)–MEK–ERK and EGFR-HER2 pathways to achieve maximal therapeutic efficacy in patients.
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影响因子：
12.6
作者：
Furukawa, Toru
通讯作者：
Furukawa, Toru
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
50.3
作者：
Navas C;Hernández-Porras I;Schuhmacher AJ;Sibilia M;Guerra C;Barbacid M
通讯作者：
Barbacid M
DOI：
10.1073/pnas.1313857110
发表时间：
2013-09-17
影响因子：
11.1
作者：
Maron, Ruth;Schechter, Bilha;Sela, Michael
通讯作者：
Sela, Michael
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA