Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance.

EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC. The HNSCC cell line, CAL33 was sensitive to gefitinib but resistant to cetuximab. Cetuximab induces an unexpected EGFR phosphorylation in CAL33 cells similarly to EGF but this EGFR activation does not trigger EGFR internalization/degradation, the process currently implicated in the response to cetuximab. Cetuximab inhibits ERK and AKT phosphorylation in cetuximab-sensitive A431 cells, whereas the level of AKT phosphorylation is unmodified in cetuximab-resistant cells. Interestingly, CAL33 cells harbor a PIK3CA mutation. The treatment of CAL33 cells with PI3K inhibitor and cetuximab restores the inhibition of AKT phosphorylation and induces growth inhibition. Our results indicate that EGFR internalization is impaired by cetuximab treatment in CAL33 cells and that the AKT pathway is a central element in cetuximab resistance. The combination of cetuximab with a PI3K inhibitor could be a good therapeutic option in PIK3CA-mutated HNSCC

Int. J. Oncol.

EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC. The HNSCC cell line, CAL33 was sensitive to gefitinib but resistant to cetuximab. Cetuximab induces an unexpected EGFR phosphorylation in CAL33 cells similarly to EGF but this EGFR activation does not trigger EGFR internalization/degradation, the process currently implicated in the response to cetuximab. Cetuximab inhibits ERK and AKT phosphorylation in cetuximab-sensitive A431 cells, whereas the level of AKT phosphorylation is unmodified in cetuximab-resistant cells. Interestingly, CAL33 cells harbor a PIK3CA mutation. The treatment of CAL33 cells with PI3K inhibitor and cetuximab restores the inhibition of AKT phosphorylation and induces growth inhibition. Our results indicate that EGFR internalization is impaired by cetuximab treatment in CAL33 cells and that the AKT pathway is a central element in cetuximab resistance. The combination of cetuximab with a PI3K inhibitor could be a good therapeutic option in PIK3CA-mutated HNSCC

To ventilate or not to ventilate during bystander CPR — A EuReCa TWO analysis

Background: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). Method: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. Results: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17–1.83). Conclusion: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both

To ventilate or not to ventilate during bystander CPR : a EuReCa TWO analysis

Background: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). Method: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. Results: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17–1.83). Conclusion: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both