Raut Pratima, Mathivanan Poompozhil, Batra Surinder K, Ponnusamy Moorthy P
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Cancer. 2025 Mar 7;24(1):70. doi: 10.1186/s12943-025-02247-4.
The mutation in Gsα-coding GNAS exons, popular as gsp oncogene, is the most frequent mutation across all heterotrimeric G proteins involved in oncogenesis. GNAS R201, the most frequently mutated, followed by Q227, are found predominantly across various neoplasms and cancers such as IPMN, pituitary, thyroid, appendiceal, colorectal, etc. This review emphasizes the pivotal significance of the gsp oncogene and its ramifications underpinning the sustained addiction to GNAS mutation. Recent studies delineating the mechanistic intricacies that provide solid evidence of the profound impact of oncogenic GNAS on tumor formation, progression, and maintenance are highlighted. We have leveraged the discoveries of Gsα as an ideal neoantigen candidate for vaccine therapy, allele-specific inhibitors, and cyclic peptide-based small molecular inhibitors for G proteins and explored the therapeutic potential to target oncogenic GNAS directly. Alternative therapeutic modalities and patient-centric studies to mitigate the impact of GNAS mutations are also discussed. The exposition of novel studies and strategies designed to address the potential challenges inherent in these approaches of targeting the activating mutations of GNAS, along with probable avenues for further investigation, are highlighted. This review aims to reverberate the current understanding of the oncogenic potential of GNAS, the genomic and biological landscape of GNAS-driven neoplasms and cancers, and potential therapeutic strategies against them.
编码Gsα的GNAS外显子中的突变，即广为人知的gsp癌基因，是参与肿瘤发生的所有异源三聚体G蛋白中最常见的突变。最常发生突变的GNAS R201，其次是Q227，主要见于各种肿瘤和癌症，如胰腺导管内乳头状黏液性肿瘤（IPMN）、垂体、甲状腺、阑尾、结肠直肠等。本综述强调了gsp癌基因的关键意义及其对持续依赖GNAS突变的影响。重点介绍了最近的研究，这些研究阐明了致癌性GNAS对肿瘤形成、进展和维持产生深远影响的机制复杂性。我们利用了将Gsα作为疫苗治疗的理想新抗原候选物、等位基因特异性抑制剂以及基于环肽的G蛋白小分子抑制剂的发现，并探索了直接靶向致癌性GNAS的治疗潜力。还讨论了减轻GNAS突变影响的替代治疗方式和以患者为中心的研究。突出了旨在应对靶向GNAS激活突变这些方法中固有潜在挑战的新研究和策略阐述，以及可能的进一步研究途径。本综述旨在反映当前对GNAS致癌潜力、GNAS驱动的肿瘤和癌症的基因组及生物学概况以及针对它们的潜在治疗策略的理解。
