The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
Renal blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) is a noninvasive fast technique to characterize renal function. Here we evaluated the impact of renal function on the relaxation rate (R2(*)) in the cortex and medulla to provide baseline data for further use of renal BOLD-MRI. This parameter was evaluated in 400 patients scheduled for abdominal imaging who underwent transversal blood oxygen level-dependent measurements with a multi-echo gradient-echo sequence with 12 echo times. The loss of phase coherence (T2(*)) maps were generated in which kidney regions of interest were selected to differentiate the medulla and cortex, and R2(*) was equated to 1/T2(*). Individual R2(*) values were, in turn, correlated to the eGFR (MDRD formula of 280 patients with available serum creatinine measurements), age, and gender each for 1.5 and 3.0 T field-strength scans of 342 patients. At both the field strengths, no significant differences in R2(*) of the cortex and medulla were found between patient gender, age, eGFR, or between different stages of chronic kidney disease determined using the KDOQI system. Thus, BOLD-MRI of a non-specific patient population failed to discriminate between the patients with various stages of chronic kidney disease.
This study demonstrates the physiologic evaluation of human kidneys with 3-T (23)Na MR imaging. The (23)Na imaging technique used allows the quantification of the corticomedullary (23)Na concentration and the assessment of its change with differing physiologic conditions.
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