Exploiting cancer’s phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy

Abstract

Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or ‘corrected’ through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy.

Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy

“…'Neuropeptide hormones and their receptors are known to be involved in the oncogenic transformation process in various cancers [24]. Ectopic expression of AVP and its receptors has been reported in prostate, colon, breast, small cell lung carcinoma, gastrointestinal, and head and neck cancers [28,29]. An abnormal splice variant of V2R, which could negatively regulate normal V2 receptors has also been reported [29,30].…”

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

“…G-protein-coupled receptors (GPCRs) constitute a large family of diverse receptors that play crucial roles in the function of normal tissues through the activation of intracellular signaling pathways in response to specific extracellular signals [ 28 ]. GPCRs have been found to play an important role in tumorigenesis and cancer progression and have been reported to be overexpressed in human NSCLC [ 42 , 43 ]. Therefore, therapeutic approaches targeting GPCRs in metastatic NSCLC have been developed, and their efficacy is currently under investigation [ 44 , 45 ].…”

Neuropeptide G Protein-Coupled Receptors as Oncotargets

“…High affinity non-peptide antagonists need to be developed for PAC1 VPAC1 and VPAC2. The use of peptide coated nanoparticles which contain chemotherapeutics is being investigated ( 137 ). The GPCR can be used to direct neuropeptide coated nanoparticle to the tumor.…”