Effect of KRAS exon 2 mutations on antitumor activity of afatinib and gefitinib. Issue 4 (April 2015)

• Record Type: Journal Article
• Authors: Gamba, Sebastian; Camaj, Peter; Heinemann, Volker; Laubender, Rüdiger P.; Wang, Yan; Zhao, Yue; Stintzing, Sebastian; Giessen, Clemens; Boeck, Stefan; Haertl, Christoph; Bruns, Christiane J.; Modest, Dominik P.
• Is Part Of: Anti-cancer drugs. Volume 26:Issue 4(2015)
• Publication Date: 2015-04
• Subjects: Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000196
• Languages: English
• ISSNs: 0959-4973

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p>The aim of this study was to investigate the impact of different <italic>KRAS</italic> mutations on the inhibitory potential of afatinib and gefitinib in SW48 colorectal cancer cells. The influence of afatinib/gefitinib on cell viability and cell cycle was evaluated in isogenic SW48 <italic>KRAS</italic> wild-type/mutant cells. Protein levels of phosphorylated/total EGFR, HER-2, HER-3, ERK, and AKT were compared between treated/untreated samples using western blotting. The activity of both afatinib and gefitinib was the lowest in <italic>KRAS</italic> G12C/G12S/G12D and the highest in G13D/G12A mutant subtypes. A 50% decrease in cell viability was achieved at concentrations of 3.0–7.7 μmol/l for afatinib and 5.4–19.5 μmol/l for gefitinib. The effect of both drugs on apoptosis appeared to be stronger than their influence on proliferation and was generally less pronounced in mutant cells than in wild-type cells. The average number of apoptotic cells after treatment with afatinib was 2.6 times as high as the corresponding value following treatment with gefitinib (<italic>P</italic><0.01). Levels of pEGFR, pHER-2, pERK, and pAKT were reduced more extensively by afatinib than by gefitinib (<italic>P</italic><0.001). Some <italic>KRAS</italic> mutations (G12C/G12S/G12D) appear to weaken the activity of afatinib and gefitinib whereas others seem to increase sensitivity to treatment (G13D/G12A) compared with the parental clone (<italic>KRAS</italic> wild-type). In SW48 colorectal cancer cells, afatinib seems to be more potent than gefitinib because of its superior efficacy in inhibiting both EGFR and HER-2, suppressing signaling along both MEK/ERK and PI3K/AKT pathways to a greater extent.</p> </sec> </abstract>