Lasting response by vertical inhibition with cetuximab and trametinib in KRAS-mutated colorectal cancer patient-derived xenografts

被引:4
|
作者
Reissig, Timm M. [1 ,2 ,3 ]
Ladigan-Badura, Swetlana [1 ,4 ]
Steinberg, Anja [1 ]
Maghnouj, Abdelouahid [1 ]
Li, Ting [1 ]
Verdoodt, Berlinda [5 ]
Liffers, Sven T. [3 ,5 ]
Pohl, Michael [4 ]
Wolters, Heiner [6 ]
Teschendorf, Christian [6 ]
Viebahn, Richard [7 ]
Admard, Jakob [8 ]
Casadei, Nicolas [8 ]
Tannapfel, Andrea [5 ]
Schmiegel, Wolff [4 ]
Hahn, Stephan A. [1 ,10 ]
Vangala, Deepak B. [1 ,4 ,9 ]
机构
[1] Ruhr Univ Bochum, Fac Med, Dept Mol GI Oncol, Bochum, Germany
[2] Univ Hosp Essen, West German Canc Ctr, Dept Med Oncol, Essen, Germany
[3] Univ Duisburg Essen, Univ Hosp Essen, Bridge Inst Expt Tumor Therapy, West German Canc Ctr, Duisburg, Germany
[4] Ruhr Univ Bochum, Univ Hosp Knappschaftskrankenhaus, Ctr Hematooncol Dis, Bochum, Germany
[5] Ruhr Univ Bochum, Inst Pathol, Bochum, Germany
[6] St Josef Hosp, Dept Visceral & Gen Surg, Dortmund, Germany
[7] Ruhr Univ Bochum, Univ Hosp Knappschaftskrankenhaus, Dept Visceral & Gen Surg, Bochum, Germany
[8] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany
[9] Ruhr Univ Bochum, Univ Hosp Knappschaftskrankenhaus, Dept Hematol & Oncol, D-44892 Bochum, Germany
[10] Ruhr Univ Bochum, Ctr Clin Res, Univ Str 150, D-44801 Bochum, Germany
关键词
CRC; EGFR; MEK; PDX; resistance; targeted therapy; FOLFIRI PLUS BEVACIZUMAB; ACQUIRED-RESISTANCE; ANTITUMOR EFFICACY; GENOMIC LANDSCAPE; OPEN-LABEL; ACTIVATION; SELUMETINIB; IRINOTECAN; MUTATIONS; DISCOVERY;
D O I
10.1002/1878-0261.13510
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumours with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; <= - 30%), stable disease (SD; between -30% and +20%) or progressive disease (PD; >= + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.
引用
收藏
页码:2396 / 2414
页数:19
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