MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC.

Epidermal growth factor receptor (EGFR) inhibitors are highly effective in treating non-small cell lung cancers (NSCLC) expressing activated EGFR, particularly those harboring EGFR mutations.  However, most patients who benefit from EGFR inhibitors achieve only partial responses or stable disease, facilitating the emergence of resistance.  Thus, progression-free survival advantages in responding patients are modest.  Combination therapy, preferably using agents with synergistic activity, could both improve responses and reduce acquired resistance rates.   We hypothesized that combining MEK inhibitors with EGFR inhibitors could result in such a benefit.  The MAPK pathway lies downstream of EGFR and transduces both proliferative and survival signals in a variety of cancer types.  Inhibitors of this pathway are currently in clinical trials, but little evidence exists supporting the use of these agents as monotherapy in EGFR-dependent non-small cell lung cancer.   In this study, we find EGFR-dependent NSCLC cell lines are moderately sensitive to loss of ERK1/2 activity, either by small molecule inhibition or by siRNA knockdown.  The consequence of inhibition is dependent upon the trophic content of the culture media, primarily anti-proliferative in serum-rich conditions and pro-apoptotic in serum-poor conditions. However, when ERK inhibition combined with EGFR inhibitors, cytotoxic synergy was observed for all EGFR-dependent cell lines tested in serum-containing media.  Enhanced cytotoxicity is demonstrated in cell lines with and without EGFR mutations, including those harboring the T790M escape mutation.  These findings support future clinical studies that combine EGFR- and MEK1/2-targeted agents to investigate whether improved outcomes can be achieved in clinically screened EGFR-dependent NSCLC.

An innovative method for preparation for rural practice: the high school rural scholars program.

Recent studies have shown that the most effective strategy to increase the number of practicing rural physicians is to admit more students with affinity for rural practice to medical school. A significant limitation of this strategy is the generally lower scores made on standardized tests by those from smaller high schools in rural areas. Although once admitted these students perform on a par with their urban counterparts, admission remains an obstacle for many. This report summarizes the second year of an innovative program that placed rising high school seniors in shadowing opportunities in their home towns while providing preparation for the ACT exam in a virtual classroom environment. Results show that the 20 students involved increased their knowledge of the strengths and weaknesses of health care in their towns as well as their understanding of how various health professionals function. The ACT composite score increased by 1.2 points, to 23. The reading and science subscores showed the largest increase. Although labor-intensive for the coordinators, the program was successful in meeting the stated goals.