Purpose: Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14-mutant NSCLC.Experimental Design: Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).Results: A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14mutant allele, were observed in 7 patients (35%). A number of offtarget mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on-and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.Conclusions: On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.

◥Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.Significance: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance.

Introduction: Capmatinib is approved for MET exon 14altered NSCLC on the basis of activity in targeted therapynaive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor.Methods: Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received

PURPOSE Genomic testing is recognized in national guidelines as essential to guide appropriate therapy selection in metastatic colorectal cancer. Previous studies report adherence to testing guidelines is suboptimal, but current testing rates have not been assessed. This study reports testing rates in metastatic colon cancer (mCC) for guideline-recommended biomarkers in a US-based population. MATERIALS AND METHODS A retrospective review of data extracted from electronic medical records was performed to identify patients with pathologically confirmed mCC and describe patterns of guideline-aligned biomarker testing. Data were extracted from the electronic health records of 1,497 patients treated at 23 practices across the United States. Both community and academic centers were represented. RESULTS A total of 1,497 patients with mCC diagnosed between January 1, 2013 and December 31, 2017 were identified. Guideline-aligned biomarker testing rates for RAS, BRAF, and microsatellite instability/mismatch repair deficiency over this study period were 41%, 43%, and 51%, respectively. Patients were more likely to have guideline-aligned testing for RAS and BRAF if they were treated at an academic center, were diagnosed with de novo metastatic disease, and were female. In addition, patients < 65 years of age were more likely to have guideline-aligned RAS testing. Of the 177 patients (12% of cohort) who received anti–epidermal growth factor receptor therapy, only 50 (28%) had complete guideline-aligned biomarker testing. CONCLUSION Despite guideline recommendations and significant therapeutic implications, overall biomarker testing rates in mCC remain suboptimal. Adherence to guideline-recommended biomarker testing would potentially reduce exposure to expensive and ineffective therapies, resulting in improved patient outcomes.

High oleic cultivars are becoming increasing prevalent in the peanut industry due to their increased shelf life compared to conventional cultivars. High oleic peanuts are typically defined as having oleic acid/linoleic acid (O/L) ratios ≥ 9, whereas most traditional varieties have O/L ratios near 1.5-2.0. In practice, this ratio can vary substantially among commercial material; accordingly, the goal of this study was to better understand the shelf life and physical properties of 16 model oil blends with O/L ratios systematically prepared from 1.3-38.1. Across these samples, % oleic acid, % linoleic acid, refractive index, density and dynamic viscosity were all highly (R2 > 0.99) linearly correlated. Increasing concentrations of oleic acid and corresponding decreases in linoleic acid were associated with decreasing oil density, decreasing refractive index, and increasing viscosity. Oxidative stability index (OSI), an established method for predicting relative oil shelf life, increased more than 7X from an O/L of 1.3 to 33.8 and this response was well described by a 2nd order polynomial. Oil stability was also assessed by storing oil blends at 24°C/50% R.H. for 24 weeks and periodically sampling these oils to measure peroxide value (PV) and describe oil flavor via sensory analysis. Excellent correlations were observed among O/L chemistry and off-flavor (oxidized/cardboard/rancid) development during storage, PV development during storage, and OSI. While viscosity was greatest for high oleic samples when comparing fresh oils, after storage under abusive conditions oil viscosity increased exponentially with decreasing O/L ratio due to oxidation/polymerization reactions. Overall, these data and observations will aid processors in selection of high O/L peanuts for various food applications and better determine final product shelf life.