◥Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRAS G12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance.Experimental Design: A panel of KRAS G12C cell lines were treated with the KRAS G12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRAS G12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy. Results:We observed rapid adaptive RAS pathway feedback reactivation following KRAS G12C inhibition in the majority of KRAS G12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRAS G12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRAS G12C /SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo.Conclusions: These data identify feedback reactivation of wildtype RAS as a key mechanism of adaptive resistance to KRAS G12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRAS G12C inhibitors. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):
Previous studies in humans have shown that the ingestion of lecithin can alter plasma cholesterol and triglyceride concentrations by mechanism(s) that remain to be elucidated. To further explore this response to lecithin, hyperlipemic rhesus monkeys were selected from a group of animals fed a semipurified diet containing corn oil, casein, sucrose and cholesterol (120 mg/100 Kcal) for 10 years. Soybean lecithin (92% phosphatidylcholine) was supplemented in the diet (0.5 g/100 Kcal) of these monkeys. Measurements of plasma cholesterol, triglycerides and phospholipid were made prior to, during and following 7 wk of lecithin supplementation. In addition, determinations of triglyceride secretion rates following administration of Triton WR1339, triglyceride clearance after intravenous infusion of Intralipid® and plasma lecithin:cholesterol acyl transferase enzyme (LCAT) activity were assessed at the same time intervals. As in other studies, manipulation of lecithin intake elicited a highly variable response, but significant changes were observed in plasma cholesterol and triglycerides as a consequence of supplementing or removing lecithin from the diet. Lecithin had no influence on the absolute plasma phospholipid level or LCAT activity. However, lecithin significantly reduced total lipids, increased the relative concentration of phospholipid and tended to increase the phospholipid/free cholesterol (PL/FC) concentration. While lecithin did not significantly affect triglyceride secretion rates, all animals were able to clear Intralipid® (triglyceride) more efficiently while fed lecithin. These data are interpreted to mean that the reduction in plasma lipids associated with lecithin ingestion may have been mediated via enhanced clearance of lipids transported in lipoproteins of lower density, whereas the rebound following lecithin removal reflected reduced clearance of these lipids.
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