Effect of KRAS exon 2 mutations on antitumor activity of afatinib and gefitinib.

The aim of this study was to investigate the impact of different KRAS 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 KRAS 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 KRAS 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 (P<0.01). Levels of pEGFR, pHER-2, pERK, and pAKT were reduced more extensively by afatinib than by gefitinib (P<0.001). Some KRAS 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 (KRAS 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.

KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancer.

AIM: To investigate the impact of KRAS mutation variants on the activity of regorafenib in SW48 colorectal cancer cells. MATERIALS & METHODS: Activity of regorafenib was evaluated in isogenic SW48 KRAS wild-type (WT) and mutant cells. Subcutaneous xenografts (KRAS WT and G12C mutant variants) in NOD/SCID mice were analyzed to elucidate the effect of regorafenib treatment in vivo. RESULTS: Compared with KRAS WT cells, all mutant variants seemed associated with some degree of resistance to regorafenib-treatment in vitro. In vivo, activation of apoptosis (TUNEL) and reduction of proliferation (Ki67) after treatment with regorafenib were more pronounced in KRAS WT tumors as compared with G12C variants. CONCLUSION: In SW48 cells, exon 2 mutations of the KRAS gene may influence antitumor effects of regorafenib.

Radiographically occult perforation and dissection of the common carotid artery following stab injury to the neck.

In recent years, many diagnostic algorithms have been devised to reduce the rate of negative explorations associated with indiscriminate surgical management of penetrating neck injuries. In hemodynamically stable patients, the need for surgical intervention is usually determined by integrating both clinical signs and radiological findings; if such investigations remain unremarkable, recommended treatment consists in close observation and sequential physical examinations. We report on a 29-year-old male who was admitted to a Swiss tertiary care hospital after sustaining a penetrating injury to his left neck following a knife attack. Disregarding a pre-hospital account of hemorrhage from the wound and slight dysphagia, no manifest symptoms or signs of internal organ damage were present on primary survey. Moreover, there was no evidence of vascular or aerodigestive tract injury on initial CT angiography. We nonetheless proceeded with immediate surgical exploration, exposing a significant perforation of the left common carotid artery with concomitant dissection of the said vessel. Surgical repair was successfully performed and the patient suffered no long-term sequelae. We thus recommend that a high level of suspicion be upheld in both asymptomatic and oligosymptomatic patients with PNI and that clinical practitioners remain cautious in the face of deceptively reassuring radiologic findings.