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Small cell lung cancer (SCLC) has a high degree of plasticity and is characterized by a remarkable response to chemotherapy followed by the development of resistance. Here, we use a mouse SCLC model to show that intratumoral heterogeneity of SCLC is progressively established during SCLC tumorigenesis. YAP/TAZ and Notch are required for the generation of non-neuroendocrine (Non-NE) SCLC tumor cells, but not for the initiation of SCLC. YAP signals through Notch-dependent and Notch-independent pathways to promote the fate conversion of SCLC from NE to Non-NE tumor cells by inducing Rest expression. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells, while the inactivation of YAP in Non-NE SCLC tumor cells switches cell death induced by chemotherapy drugs from apoptosis to pyroptosis. Our study demonstrates that YAP plays critical roles in the establishment of intratumoral heterogeneity and highlights the potential of targeting YAP for chemoresistant SCLC.

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AimsTo simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready‐to‐use autoinjector with a Miglyol diluent (exenatide QWS‐AI). This study compared the efficacy and safety of exenatide QWS‐AI with the first‐in‐class glucagon‐like peptide‐1 receptor agonist exenatide twice daily (BID).Materials and MethodsThis randomized, open‐label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose‐lowering medication randomized patients 3:2 to either exenatide QWS‐AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28‐week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments.ResultsA total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2; diabetes duration, 8.5 years) received either exenatide QWS‐AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by −1.4% and −1.0%, respectively (least‐squares mean difference, −0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS‐AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS‐AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS‐AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use.ConclusionsExenatide QWS‐AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.