1.
ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway.
Ou, SH, Tan, J, Yen, Y, Soo, RA
Expert review of anticancer therapy. 2012;(4):447-56
Abstract
ROS1 is one of 58 receptor tyrosine kinases, and one of two orphan receptor tyrosine kinases where its ligand is unknown. ROS1 is evolutionarily related to ALK. ROS1 rearrangement was discovered in glioblastoma in 1987, in non-small-cell lung cancer (NSCLC) in 2007, and in cholangiocarcinoma in 2011. While the clinicopathologic characteristics of ROS1-rearranged glioblastoma and cholangiocarcinoma patients remain to be defined, the clinicopathologic characteristics of ROS1-rearranged NSCLC patients have recently been described. Although ROS1 shares only 49% amino acid sequence homology with ALK in the kinase domains, several ALK inhibitors have demonstrated in vitro inhibitory activity against ROS1. With the recent US approval of crizotinib, a multi-targeted ALK/MET kinase inhibitor, for the treatment of ALK-rearranged NSCLC, attention has turned to ROS1-rearranged tumors, especially NSCLC. The next few years should witness a rapid pace of clinical research in ROS1-rearranged tumors utilizing available ALK inhibitors.
2.
Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling.
Rabkin, R, Sun, DF, Chen, Y, Tan, J, Schaefer, F
Pediatric nephrology (Berlin, Germany). 2005;(3):313-8
Abstract
Resistance to growth hormone (GH) is a significant complication of advanced chronic renal failure. Thus while the circulating GH levels are normal or even elevated in uremia, resistance to the hormone leads to stunting of body growth in children and contributes to muscle wasting in adults. Insensitivity to GH is the consequence of multiple defects in the GH/insulin-like growth factor-1 (IGF-1) system. Expression of the GH receptor may be reduced, although this is not a consistent finding, GH activation of the Janus kinase 2-signal transducer (JAK2) and activator of transcription (STAT) signal transduction pathway is depressed and this leads to reduced IGF-1 expression, and finally there is resistance to IGF-1, a major mediator of GH action. We review these various defects with an emphasis on the GH-activated JAK2-STAT5 pathway, since this pathway is essential for normal body growth and there has been recent progress in our understanding of the perturbations that occur in uremia.