👤 S Riedl

Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC) with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, where EGFR-mediated RAS-MAPK pathway reactivation can be targeted toimprove response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear. Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models. We observed RTK-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models, but limited to those with epithelial differentiation. Conversely, adaptive RAS MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from TCGA, EGFR and ERBB3 expression was highly correlated with expression of epithelial markers, while expression of FGFR1 and mesenchymal markers were correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared to combinations of KRASi and EGFR blockade. In PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in PDAC patients. Show less

The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC Show less

We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (-4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12-15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described. Show less