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The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1–5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2–Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.

BackgroundThe study was conducted to evaluate the feasibility of using malignant pleural effusion (MPE) as a substitute specimen for genetic testing and to determine the significance of genetic profiling of MPE tumor cells to monitor non‐small cell lung cancer (NSCLC) progression and therapeutic response.MethodsWe selected 168 NSCLC patients with MPE. We extracted MPE and enriched tumor cells using a custom‐designed device. EGFR mutations and ALK/ROS1 fusions were then detected by quantitative real‐time PCR, and the results were used to guide targeted therapy. We investigated drug responses through imaging.ResultsMPE tumor cells were detected in all patients. EGFR mutations and ALK/ROS1 rearrangements were detected in biopsy samples, treated MPE, and untreated MPE. We found that treated MPE had higher sensitivity and specificity than biopsy or untreated MPE. Among the 26 EGFR inhibitor patients, 13 showed a partial response, 7 had progressive disease, and 6 showed stable disease. Among the 16 patients that received ALK/ROS1 inhibitors, 8 had a partial response, 4 had progressive disease, and 4 showed stable disease.ConclusionOur study provides a new, less invasive, and highly repeatable method of analyzing MPE tumor cells in NSCLC that facilitates precision medicine and genetic testing.