The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. , BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants., BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting. Patients with -driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with -altered tumors, clinically validating selective RET targeting..

Emerging evidence suggests that restoration of blood flow in a stuttering manner may limit lethal myocardial ischemia-reperfusion injury. However, the mechanisms contributing to this phenomenon, termed postconditioning (post-C), remain poorly defined. Our aim was to test the hypothesis that activation of classic "survival kinases," phosphatidylinositol 3-kinase (PI3-kinase) and/or extracellular signal-regulated kinase (ERK)1/2, may play a role in post-C-induced cardioprotection. In protocol 1, isolated buffer-perfused rabbit hearts underwent 30 min of sustained coronary artery occlusion and were randomized to receive abrupt reperfusion (controls) or four cycles of 30 s of reperfusion and 30 s of reocclusion before full restoration of flow (post-C). Protocol 2 was identical except control and postconditioned hearts received the PI3-kinase inhibitor LY-294002 (protocol 2A) or the ERK1/2 antagonist PD-98059 (protocol 2B) throughout the first 25 min of reperfusion, whereas in protocol 3, myocardial samples were obtained during the early minutes of reflow from additional control, postconditioned, and nonischemic sham hearts for the assessment, by standard immunoblotting, of phospho-Akt (downstream target of PI3-kinase) and phospho-ERK. Protocols 1 and 2 corroborated that infarct size (delineated by tetrazolium staining and expressed as a percent of risk region) was reduced in postconditioned hearts vs. control hearts and also revealed that post-C-induced cardioprotection was maintained despite LY-294002 treatment but was abrogated by PD-98059. These pharmacological data were supported by protocol 3, which showed increased immunoreactivity of phospho-ERK but not phospho-Akt with post-C. Thus our results implicate the involvement of ERK1/2 rather than PI3-kinase/Akt in the reduction of infarct size achieved with post-C.

Postconditioning (PostC), or relief of myocardial ischemia in a stuttered manner, has been shown to reduce infarct size, due in part to upregulation of survival kinase signaling. Virtually all of these data have, however, been obtained in healthy adult cohorts; the question of whether PostC-induced cardioprotection is maintained in the setting of clinically relevant comorbidities has remained largely unexplored. Accordingly, our aim was to assess the consequences of a major risk factor-diabetes-on the infarct-sparing effect of stuttered reflow. Isolated buffer-perfused hearts were obtained from normoglycemic C57BL/6J mice, BKS.Cg-m+/+Lepr(db)/J (db/db) mice (model of type-2 diabetes), C57BL/6J mice injected with streptozotocin (model of type-1 diabetes), and streptozotocin-injected mice in which normoglycemia was re-established by islet cell transplantation. All hearts underwent 30  min of ischemia and, within each cohort, hearts received either standard (control) reperfusion or three to six 10-s cycles of stuttered reflow. PostC reduced infarct size via upregulation of extracellular signal-regulated kinase 1/2 in normoglycemic mice. In contrast, diabetic hearts were refractory to PostC-induced cardioprotection-an effect that, in the type-1 model, was reversed by restoration of normoglycemia. We provide novel evidence for a profound-but potentially reversible-diabetes-induced defect in the cardioprotective efficacy of PostC.

Old mouse hearts are refractory to infarct size reduction with post-conditioning, possibly because of an age-associated increase in MKP-1 and resultant deficit in ERK phosphorylation.

Summary Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib.1 The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism.2 Multiple mechanisms of this effect have been proposed, including decreased iodine organification3 and glandular capillary regression.4 Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.