Old receptors learn new tricks : biasing anti-IGF1R cancer therapy through the GPCR system

As cancers progress, tumor cells exploit the extracellular signals generated from plasma membrane receptors for cell growth, migration, and anti-apoptosis. G protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTKs) are two important families of plasm membrane receptors, controlling multiple biological functions via their downstream signaling. IGF1R, one of the major RTKs involved in developing the malignant phenotype, plays a critical role in the tumorigenesis of multiple cancers. Thus, anti-IGF1R antibodies and inhibitors soon became attractive stars in cancer treatment. Disappointingly, IGF1R lost its “glory” in clinical trials with a promising start but no happy end. However, lessons from those clinical trials led us to explore the underlying mechanisms behind anti-IGF1R cancer therapy. One of the outcomes is that IGF1R interacts with GPCR downstream modulators (G proteins, GRKs, β-arrestins), which are vital in coordinating IGF1R downstream signaling. This thesis aims to refine the concept of IGF1R targeting through GPCR components and translate it into clinical application.

In Study 1, we investigated the potential therapeutic mechanisms of the IGF1R/ β-arrestin /p53 axis in conjunctival melanoma (CM). This research revealed the targeted therapeutic strategy of controlling IGF1R and p53 pro/suppressor tumorigenic signals via β-arrestin1/MDM2, thus reducing tumor growth and the risk of metastasis. In Study 2, we studied the molecular mechanism of inhibiting IGF1R through “system bias”. Our work highlights unbiased downregulation of IGF1R via GRK2 inhibition in Ewing’s sarcoma. These findings reveal the molecular and biological roles of biased signaling downstream of IGF1R and its potential therapeutic application in clinical settings. In Study 3, we investigated the therapeutic strategies of targeting IGF1R via “system bias” in colorectal cancer. This work demonstrated that paroxetine (PX) could downregulate both IGF1R and the epidermal growth factor receptor (EGFR), resulting in inhibition of cancer cell viability. When combining PX with MAPK and PI3K inhibitors, the combination treatment showed an additive inhibition effect on tumor growth and metastasis. This study revealed a strategy of controlling signaling pathways residual to system bias inhibition. In Study 4, we studied the involvement of G proteins in the IGF1R system. We revealed that G protein signaling regulates IGF-induced cell growth in both in vivo and in vitro experiments and their inhibition induces receptor internalization via the GRK/β-arrestin system. This study expanded the RTK-GPCR dualism paradigm of the IGF1R and explored the concept of G-protein signaling targeting in cancer.

To summarize, our studies highlight the potential of targeting IGF1R via the GRK/β-arrestin system and suggest the possibility of clinical translation of this novel concept into different cancer types. These findings broaden our understanding of the IGF1R system and open a brand-new chapter in anti-IGF1R cancer therapy.

List of scientific papers

I. Crudden C, Shibano T, Song D, Dragomir MP, Cismas S, Serly J, Nedelcu D, Fuentes-Mattei E, Tica A, Calin GA, Girnita A, Girnita L. Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth. Cancer Res. 2021 Jan 15;81(2):501-514.
https://doi.org/10.1158/0008-5472.CAN-20-1662

II. Song D, Cismas S, Crudden C, Trocme E, Worrall C, Suleymanova N, Lin T, Zheng H, Seregard S, Girnita A, Girnita L. IGF1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma. Oncogene. 2021 Nov 17.
https://doi.org/10.1038/s41388-021-02111-x

III. Song D, Takashi S, Wang X, Pasca S, Zhang S, Cismas S, Crudden C, Girnita A, Calin GA, Girnita L. G protein-coupled receptor kinase 2/β-arrestin-1 system bias inhibition of IGF1R/EGFR induces sensitization of the InsR receptor and destabilizes the metastatic phenotype of colorectal carcinoma. [Manuscript]

IV. Song D, Cismas S, Pasca S, Zhang S, Wang X, Crudden C, Takashi S, Girnita A, Calin GA, Girnita L. G protein activation balance the signaling pathways downstream insulin-like growth factor 1 receptor: therapeutic implications for cancer. [Manuscript]