Table Info

Table 1.

Phosphotyrosine residues of CSF1R and their role in oncogenesis

Phospho-tyrosine residue (CSF1R)	Mechanism of action	Cancer	Manifestation	References
Y561	SFK activation	Lung, breast	Disruption of cell-cell adhesion via loss of E-cadherin resulting in anchorage-independent growth, motility and survival. DNA synthesis and cytoskeletal reorganization.	[13–20]
Y571	Kinase activation	HM (AML, aMPN)	Phosphorylation causes kinase activation. Mutated CSF1R-Y571D results in constitutively activated receptor.	[21, 22]
Y699	MAPK pathway	PTCL	Triggers the association of adapter proteins such as Grb2, Mona and Socs1 initiates monocyte differentiation. Cell proliferation.	[23]
Y708	STAT activation	FDC-P1 cell line	Mediates responses to interferons (IFNs), and activates macrophage cell proliferation.	[24, 25]
Y723	PI3K activation	Carcinoma	Mediates p85 subunit of PI3K association with CSF1R. Regulates adhesion, actin polymerization resulting in macrophage motility and invasion.	[9]
Y809	Tyrosine kinase activation	Fibroblasts	CSF1-induced autophosphorylation of CSF1R. Serves as a binding site for STAT proteins.	[10]

HM: hematological malignancies; AML: acute myeloid leukemia; aMPN: atypical myeloproliferative neoplasms; PTCL: peripheral T cell lymphoma; FDC-P1: factor dependent continuous-paterson 1

Declarations

Author contributions

ZA: Conceptualization, Writing—original draft, Writing—review & editing, Investigation, Methodology. RPG: Supervision, Writing—review & editing. AR: Project administration. ZR: Data curation, Software, Validation.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

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Copyright

References

Jin J, Wu X, Yin J, Li M, Shen J, Li J, et al. Identification of genetic mutations in cancer: challenge and opportunity in the new era of targeted therapy. Front Oncol. 2019;9:263. [DOI] [PubMed] [PMC]

Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, et al. Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol. 2010;17:1241–9. [DOI] [PubMed]

Schubert C, Schalk-Hihi C, Struble GT, Ma HC, Petrounia IP, Brandt B, et al. Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors*. J Biol Chem. 2007;282:4094–101. [DOI] [PubMed]

Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6:a021857. [DOI] [PubMed] [PMC]

Coussens L, Van Beveren C, Smith D, Chen E, Mitchell RL, Isacke CM, et al. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature. 1986;320:277–80. [DOI] [PubMed]

Hampe A, Shamoon BM, Gobet M, Sherr CJ, Galibert F. Nucleotide sequence and structural organization of the human FMS proto-oncogene. Oncogene Res. 1989;4:9–17. [PubMed]

Rothwell VM, Rohrschneider LR. Murine c-fms cDNA: cloning, sequence analysis and retroviral expression. Oncogene Res. 1987;1:311–24. [PubMed]

Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017;5:53. [DOI] [PubMed] [PMC]

Sampaio NG, Yu W, Cox D, Wyckoff J, Condeelis J, Stanley ER, et al. Phosphorylation of CSF-1R Y721 mediates its association with PI3K to regulate macrophage motility and enhancement of tumor cell invasion. J Cell Sci. 2011;124:2021–31. [DOI] [PubMed] [PMC]

10.

Novak U, Harpur AG, Paradiso L, Kanagasundaram V, Jaworowski A, Wilks AF, et al. Colony-stimulating factor 1-induced STAT1 and STAT3 activation is accompanied by phosphorylation of Tyk2 in macrophages and Tyk2 and JAK1 in fibroblasts. Blood. 1995;86:2948–56. [PubMed]

11.

Baghdadi M, Endo H, Takano A, Ishikawa K, Kameda Y, Wada H, et al. High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers. Sci Rep. 2018;8:418. [DOI] [PubMed] [PMC]

12.

Dey A, She H, Kim L, Boruch A, Guris DL, Carlberg K, et al. Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression. Mol Biol Cell. 2000;11:3835–48. [DOI] [PubMed] [PMC]

13.

Alvarez RH, Kantarjian HM, Cortes JE. The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer. 2006;107:1918–29. [DOI] [PubMed]

14.

Amanchy R, Zhong J, Molina H, Chaerkady R, Iwahori A, Kalume DE, et al. Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays. J Proteome Res. 2008;7:3900–10. [DOI] [PubMed] [PMC]

15.

Courtneidge SA. Role of Src in signal transduction pathways. The Jubilee Lecture. Biochem Soc Trans. 2002;30:11–7. [PubMed]

16.

Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009;69:9498–506. [DOI] [PubMed] [PMC]

17.

Yeatman TJ. A renaissance for SRC. Nat Rev Cancer. 2004;4:470–80. [DOI] [PubMed]

18.

Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004;165:263–73. [DOI] [PubMed] [PMC]

19.

Knowlton ML, Selfors LM, Wrobel CN, Gu TL, Ballif BA, Gygi SP, et al. Profiling Y561-dependent and -independent substrates of CSF-1R in epithelial cells. PLoS One. 2010;5:e13587. [DOI] [PubMed] [PMC]

20.

Flick MB, Sapi E, Perrotta PL, Maher MG, Halaban R, Carter D, et al. Recognition of activated CSF-1 receptor in breast carcinomas by a tyrosine 723 phosphospecific antibody. Oncogene. 1997;14:2553–61. [DOI] [PubMed]

21.

Chase A, Schultheis B, Kreil S, Baxter J, Hidalgo-Curtis C, Jones A, et al. Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1. Leukemia. 2009;23:358–64. [DOI] [PubMed]

22.

Walter M, Lucet IS, Patel O, Broughton SE, Bamert R, Williams NK, et al. The 2.7 Å crystal structure of the autoinhibited human c-Fms kinase domain. J Mol Biol. 2007;367:839–47. [DOI] [PubMed]

23.

Murga-Zamalloa C, Rolland DCM, Polk A, Wolfe A, Dewar H, Chowdhury P, et al. Colony-stimulating factor 1 receptor (CSF1R) activates AKT/mTOR signaling and promotes T-cell lymphoma viability. Clin Cancer Res. 2020;26:690–703. [DOI] [PubMed] [PMC]

24.

Novak U, Nice E, Hamilton JA, Paradiso L. Requirement for Y706 of the murine (or Y708 of the human) CSF-1 receptor for STAT1 activation in response to CSF-1. Oncogene. 1996;13:2607–13. [PubMed]

25.

Meissl K, Macho-Maschler S, Müller M, Strobl B. The good and the bad faces of STAT1 in solid tumours. Cytokine. 2017;89:12–20. [DOI] [PubMed]

26.

George DM, Huntley RJ, Cusack K, Duignan DB, Hoemann M, Loud J, et al. Prodrugs for colon-restricted delivery: design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors. PLoS One. 2018;13:e0203567. [DOI] [PubMed] [PMC]

27.

West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A. 2006;103:690–5. [DOI] [PubMed] [PMC]

28.

Benner B, Good L, Quiroga D, Schultz TE, Kassem M, Carson WE, et al. Pexidartinib, a novel small molecule CSF-1R inhibitor in use for tenosynovial giant cell tumor: a systematic review of pre-clinical and clinical development. Drug Des Devel Ther. 2020;14:1693–704. [DOI] [PubMed] [PMC]

29.

Kang HG, Lee SY, Jeon HS, Choi YY, Kim S, Lee WK, et al. A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females. J Thorac Oncol. 2014;9:1647–55. [DOI] [PubMed]

30.

Denton NL, Chen CY, Scott TR, Cripe TP. Tumor-associated macrophages in oncolytic virotherapy: friend or foe? Biomedicines. 2016;4:13. [DOI] [PubMed] [PMC]

31.

4R7H Crystal structure of FMS KINASE domain with a small molecular inhibitor, PLX3397 [Internet]. [cited 2022 Jul 27]. Available from: https://www.rcsb.org/structure/4r7h

32.

Edicotinib [Internet]. [cited 2020 Aug 13]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/25230468

33.

Vimseltinib [Internet]. [cited 2020 Jun 10]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/86267612

34.

c-Fms-IN-12 [Internet]. [cited 2020 Jun 16]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/67259771

35.

4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide [Internet]. [cited 2020 Jun 18]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/46184986

36.

Chiauranib [Internet]. [cited 2020 Jun 20]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/49779393

37.

Dovitinib [Internet]. [cited 2020 Oct 1]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/135398510

38.

Sorafenib [Internet]. [cited 2020 Jun 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/216239

39.

El-Gamal MI, Al-Ameen SK, Al-Koumi DM, Hamad MG, Jalal NA, Oh CH. Recent advances of colony-stimulating factor-1 receptor (CSF-1R) kinase and its inhibitors. J Med Chem. 2018;61:5450–66. [DOI] [PubMed]

40.

Peng YH, Shiao HY, Tu CH, Liu PM, Hsu JT, Amancha PK, et al. Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem. 2013;56:3889–903. [DOI] [PubMed]

41.

Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373:428–37. [DOI] [PubMed]

42.

Zhang C, Ibrahim PN, Zhang J, Burton EA, Habets G, Zhang Y, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A. 2013;110:5689–94. [DOI] [PubMed] [PMC]

43.

Hira S, Saleem U, Anwar F, Raza Z, Rehman AU, Ahmad B. In silico study and pharmacological evaluation of eplerinone as an anti-Alzheimer’s drug in STZ-induced Alzheimer’s disease model. ACS Omega. 2020;5:13973–83. [DOI] [PubMed] [PMC]

44.

Caldwell TM, Ahn YM, Bulfer SL, Leary CB, Hood MM, Lu WP, et al. Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of tenosynovial giant cell tumor (TGCT). Bioorg Med Chem Lett. 2022;74:128928. [DOI] [PubMed]

45.

Smith BD, Kaufman MD, Wise SC, Ahn YM, Caldwell TM, Leary CB, et al. Vimseltinib: a precision CSF1R therapy for tenosynovial giant cell tumors and diseases promoted by macrophages. Mol Cancer Ther. 2021;20:2098–109. [DOI] [PubMed] [PMC]

46.

Johnson M, Dudek AZ, Sukari A, Call J, Kunk PR, Lewis K, et al. ARRY-382 in combination with pembrolizumab in patients with advanced solid tumors: results from a phase 1b/2 study. Clin Cancer Res. 2022;28:2517–26. [DOI] [PubMed] [PMC]

47.

Bendell JC, Tolcher AW, Jones SF, Beeram M, Infante JR, Larsen P, et al. Abstract A252: A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers. Mol Cancer Ther. 2013;12:A252. [DOI]

48.

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. [DOI] [PubMed]

49.

Qin S, Chan LS, Gu S, Bai Y, Ren Z, Lin X, et al. LBA35 Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial. Ann Oncol. 2022;33:S1401–2. [DOI]

50.

Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:7271–8. [DOI] [PubMed]

51.

Lin CC, Gil-Martin M, Bauer TM, Naing A, Lim DWT, Sarantopoulos J, et al. Abstract CT171: Phase I study of BLZ945 alone and with spartalizumab (PDR001) in patients (pts) with advanced solid tumors. Cancer Res. 2020;80:CT171. [DOI]

52.

Almahariq MF, Quinn TJ, Kesarwani P, Kant S, Miller CR, Chinnaiyan P. Inhibition of colony-stimulating factor-1 receptor enhances the efficacy of radiotherapy and reduces immune suppression in glioblastoma. In Vivo. 2021;35:119–29. [DOI] [PubMed] [PMC]

53.

Quail DF, Joyce JA. Molecular pathways: deciphering mechanisms of resistance to macrophage-targeted therapies. Clin Cancer Res. 2017;23:876–84. [DOI] [PubMed] [PMC]

54.

Tang Y, Zhong M, Zha J, Xu B. Preclinical studies of chiauranib inhibit follicular lymphoma through VEGFR2/ERK/STAT3 signaling pathway. Blood. 2022;140:11578. [DOI]

55.

Gao T, Huang J, Yin H, Huang J, Xie J, Zhou T, et al. Inhibition of extranodal NK/T-cell lymphoma by chiauranib through an AIF-dependent pathway and its synergy with L-asparaginase. Cell Death Dis. 2023;14:316. [DOI] [PubMed] [PMC]

56.

Hasinoff BB, Wu X, Nitiss JL, Kanagasabai R, Yalowich JC. The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II. Biochem Pharmacol. 2012;84:1617–26. [DOI] [PubMed] [PMC]

57.

Sharma M, Schilero C, Peereboom DM, Hobbs BP, Elson P, Stevens GHJ, et al. Phase II study of dovitinib in recurrent glioblastoma. J Neurooncol. 2019;144:359–68. [DOI] [PubMed]

58.

Wen J, Wang S, Guo R, Liu D. CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment. Eur J Med Chem. 2023;245:114884. [DOI] [PubMed]