Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8456790 | Neoplasia | 2018 | 10 Pages |
Abstract
Recent studies in RAS wild-type (WT) metastatic colorectal cancer (mCRC) suggest that the survival benefits of therapy using anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies combined with chemotherapy are maximized when the anti-EGFR antibody is given as first-line, followed by subsequent anti-VEGF antibody therapy. We report reverse-translational research using LIM1215 xenografts of RAS WT mCRC to elucidate the biologic mechanisms underlying this clinical observation. Sequential administration of panitumumab then bevacizumab (PB) demonstrated a stronger tendency to inhibit tumor growth than bevacizumab then panitumumab (BP). Cell proliferation was reduced significantly with PB (Pâ¯<â¯.01) but not with BP based on Ki-67 index. Phosphoproteomic analysis demonstrated reduced phosphorylation of EGFR and EPHA2 with PB and BP compared with control. Western blotting showed reduced EPHA2 expression and S897-phosphorylation with PB; RSK phosphorylation was largely unaffected by PB but increased significantly with BP. In quantitative real-time PCR analyses, PB significantly reduced the expression of both lipogenic (FASN, MVD) and hypoxia-related (CA9, TGFBI) genes versus control. These results suggest that numerous mechanisms at the levels of gene expression, protein expression, and protein phosphorylation may explain the improved clinical activity of PB over BP in patients with RAS WT mCRC.
Keywords
HIFguanosine triphosphate hydrolaseRSKTGFBIFOLFIRIGTPaseCA9EphA2FolfoxmCRCLSSMVDIGF2RSCIDHMGCRDEGsqRT-PCREGFRSDSHMG-CoA reductaseMAPKPFsRibosomal s6 kinasefatty acid synthaseprogression-free survivaloverall survivalsodium dodecyl sulfateColorectal cancerMetastatic colorectal cancerHypoxia-inducible factorVascular endothelial growth factorVascular Endothelial Growth Factor (VEGF)FasnLanosterol synthaseGrowth ratehazard ratiowild-typequantitative real-time polymerase chain reactionmitogen-activated protein kinaseDifferentially expressed genesCRCCarbonic anhydrase 9insulin-like growth factor 2 receptorEpidermal growth factor receptor
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Authors
Hiroya Taniguchi, Yuji Baba, Yoji Sagiya, Masamitsu Gotou, Kazuhide Nakamura, Hiroshi Sawada, Kazunori Yamanaka, Yukiko Sakakibara, Ikuo Mori, Yukiko Hikichi, Junpei Soeda, Hideo Baba,