When the bear lost its tail : targeting the GRK/β-arrestins downstream IGF1R in non-epithelial malignancies
Plasma membrane receptors are highly specialized cell surface structures that receive extracellular information and process them into biological responses. Among them, this thesis focuses on two major receptor families: the G protein-coupled receptors (GPCR) and the receptor tyrosine kinases (RTKs). One of the most studied RTKs, IGF1R has been demonstrated to be essential for cancer development in a wide range of tissues. Recognition of IGF1R signaling hijacking by twisted malignant processes was rapidly shadowed by anti-cancer therapeutics developments, yet with disappointing results in clinical setting. Failures in past anti-IGF1R strategies required bedside to bench shift and re-evaluation of the mechanism controlling IGF1R tumorigenesis. In particular its non-canonical, kinase-independent signaling capabilities, through use of the GRKs/β-arrestins system - prominent controller of GPCR-signaling-, is today acknowledged to orchestrate IGF1R oncogenic power.
This thesis aims to explore the GRK/β-arrestin system downstream IGF1R and uncover its targeting potential as a cancer therapeutic strategy in non-epithelial cancers.
Study I describes the functional roles of GRK isoform modulation in IGF1R downregulation to develop anti-IGF1R targeting strategies via inhibition of GRK2. Our results establish the potential for clinical applicability of cross-targeting the IGF1R through pharmacological inhibition of GRK2 in Ewing sarcoma by using paroxetine, a commonly prescribed antidepressant. In Study II, we investigate the therapeutic potential of p53 activation through targeting MDM2 in conjunctival melanoma. The use of Nutlin3 to reactivate p53 via inhibition of MDM2 proved more effective than siRNA inhibition of MDM2. This suggests that the additional effect of Nutlin3 on IGF1R degradation is highly beneficial in cancer targeting. This study reveals double-hit IGF1R/p53 targeting strategy as a potent therapy for recurring and metastatic conjunctival melanoma. In study III, we investigate the disruption of the p53/MDM2/IGF1R axis via unbalancing the β-arrestin system to improve treatment response to chemotherapy in malignant melanoma. This study demonstrates novel dual therapeutic strategy in which inhibition of β-arrestin1 signaling or β-arrestin2 hyperactivation can enhance response to chemotherapy. Considering the significance of IGF1R and downstream biased signaling in blood cancer, study IV investigates the individual effect of kinase signaling versus GRK/β-arrestin signaling downstream the receptor in leukemia. Our results uncover both arms of IGF1R signaling as targets for cell proliferation and survival (kinase) and cell differentiation (GRK/β-arrestin) in acute myeloid leukemia. This work establishes the potential of targeting IGF1R kinase and/or C-terminus to induce peripheral differentiation.
In summary, the findings described in the present thesis provide new insights for the therapeutic potential of non-canonical IGF1R signaling.
List of scientific papers
I. Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth. Crudden C, Takashi S, Song D, Dragomir MP, CISMAS S, Serly J, Nedelcu D, Fuentes-Mattei, Tica A, Calin GA, Girnita A and Girnita L. Cancer Research. 2021 Jan 15;81(2):501-514.
https://doi.org/10.1158/0008-5472.CAN-20-1662
II. IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma. Dawei Song, SONIA CISMAS, Caitrin Crudden, Eric Trocme, Claire Worrall, Naida Suleymanova, Tingting Lin, Huiyuan Zheng, Stefan Seregard, Ada Girnita and Leonard Girnita. Oncogene. 2021 Nov 17.
https://doi.org/10.1038/s41388-021-02111-x
III. Competing engagement of β-arrestin isoforms balance IGF1R/p53 signaling and control response of melanoma cells to chemotherapy. SONIA CISMAS, Caitrin Crudden, Iara Trocoli, Naida Suleymanova, Sylvya Pasca, Benjamin Gebhard, Dawei Song, Shiyong Neo, Takashi Shibano, Terry J Smith, George A. Calin, Ada Girnita and Leonard Girnita. [Submitted]
IV. β-arrestin/GRK signalling downstream IGF1R prevents differentiation and promotes acute phenotype of myeloid leukemia. SONIA CISMAS, Sylvya Pasca, Catalina V. Gual, Takashi Shibano, Ada Girnita, George A. Calin and Leonard Girnita. [Manuscript]
History
Defence date
2022-12-16Department
- Department of Oncology-Pathology
Publisher/Institution
Karolinska InstitutetMain supervisor
Girnita, LeonardCo-supervisors
Calin, George; Shibano, TakashiPublication year
2022Thesis type
- Doctoral thesis
ISBN
978-91-8016-859-5Number of supporting papers
4Language
- eng