The somatostatin receptor (SSTR2) is a member of the G protein-coupled receptor (GPCR) superfamily, expressed in the central nervous system, particularly the hypothalamus, as well as the digestive system and pancreas. It has diverse effects on hormone secretion, the cell cycle, apoptosis, and angiogenesis. Expression of the somatostatin receptor SSTR2 is a hallmark of well-differentiated neuroendocrine tumors (NETs) and represents a potential therapeutic target for NETs.

Expression of SSTR2

SSTR2 is widely distributed in multiple human tissues and organs. It is widely expressed in the brain and in both α- and β-cells of the pancreas, with expression levels in the pancreas higher than those of other somatostatin receptors. It is also expressed in the kidney, jejunum, colon, and liver. In the developing nervous system, SSTR2 is expressed in the cortex, initially localized to the anterior lamina and later enriched in the outer part of the germinal zone. In the cerebellum, SSTR2 is expressed deep in the external granular layer at 19 weeks of gestation. This pattern persists until birth but disappears in adulthood.

In tumor tissues, SSTR2 is highly expressed in neuroendocrine tumors, and is also expressed in meningiomas, breast cancer, prostate cancer, and colorectal cancer.

(Data source: Uniprot)

Structure of SSTR2

SSTR2 is a seven-transmembrane protein composed of 369 amino acids, with its N-terminus located extracellularly and its C-terminus located intracellularly. Its structure adopts the typical active-state conformation of class A peptide G protein-coupled receptors (GPCRs), including a similar seven-transmembrane helix (7TM) bundle, a long β-hairpin structure formed by extracellular loop 2 (ECL2), and a conserved disulfide bond between TM3 and ECL2.

(Data source: Zhao J, et al. Nat Commun. 2023)

Signal transduction by SSTR2

Binding of SSTR2 or other somatostatin receptors to SST exerts antitumor effects, activating distinct phosphotyrosine phosphatases (PTPs)—SHP-1 and SHP-2—as well as PTPη. SHP-1 induces apoptosis by activating the transcription factor NF-κB, leading to inhibition of the anti-apoptotic effects of the MAP kinase JNK. SHP-2 activates Src, which directly interacts with PTPη, inducing its tyrosine phosphorylation and activation. PTPη dephosphorylates intracellular effectors involved in cell cycle progression, such as ERK and the PI3K/Akt pathway, leading to upregulation of the cyclin kinase inhibitors p27 and p21 and the tumor suppressor gene Zac1.

After SST binds to SSTR2, it inhibits the secretion/synthesis of multiple hormones by inhibiting voltage-dependent Ca ²⁺ channels and activating K ⁺ channels, thereby reducing intracellular Ca ²⁺ concentration and inhibiting adenylate cyclase, lowering intracellular cAMP levels, thereby preventing the activation of oncogenes and inhibiting the occurrence and progression of tumors.

(Data source Eychenne R, et al. Molecules. 2020)

Targeted therapy for SSTR2

Currently, the main treatments targeting SSTR2 are radionuclide therapy and synthetic peptides. The radionuclide therapy targeting SSTR2 that has been approved for marketing is Lutetium Dotatate LU-177. In addition, there are a large number of radionuclide therapies in the clinical research stage.

[177Lu]Lu-DOTA-TATE was approved for marketing in 2017 for the treatment of neuroendocrine tumors. The molecular basis of this therapy is the internalization and retention of a radiolabeled somatostatin analog in the lysosomes of cells expressing SSTR-2. Following cellular internalization, beta-irradiation leads to intracellular DNA strand breaks and cell death, and also produces low-energy gamma radiation, enabling imaging. Therefore, tumors and their metastases express SSTR and demonstrate robust uptake in somatostatin receptor imaging, which is crucial for the efficacy of this therapy.

(Data source: Del Olmo-Garcia MI, et al. Biomedicines. 2021)

CS-5005 is an antibody-drug conjugate targeting SSTR2, currently in preclinical development by CStone Pharmaceuticals for the treatment of solid tumors. CStone Pharmaceuticals is also developing a bispecific antibody targeting SSTR2, CS-2012, in preclinical development for the treatment of solid tumors.

Tidutamab is a bispecific T cell engager targeting SSTR2/CD3 developed by Xencor, but its development has been terminated due to its poor efficacy.