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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Gastrointestinal Stromal Tumor | Research article

Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor

Authors: Dengyang Zhang, Chunxiao He, Yao Guo, Jianfeng Li, Bo Li, Yuming Zhao, Liuting Yu, Zhiguang Chang, Hanzhong Pei, Ming Yang, Na Li, Qi Zhang, Yulong He, Yihang Pan, Zhizhuang Joe Zhao, Changhua Zhang, Yun Chen

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Gastrointestinal stromal tumor (GIST) is a rare type of cancer that occurs in the gastrointestinal tract. The majority of GIST cases carry oncogenic forms of KIT, the receptor for stem cell factor (SCF). Small molecule kinase inhibitor imatinib is effective in prolonging the survival of GIST patients by targeting KIT. However, drug resistance often develops during the therapeutic treatment. Here, we produced a SCF-emtansine drug conjugate (SCF-DM1) with favorable drug efficacy towards GIST cells.

Methods

Recombinant human SCF (rhSCF) was expressed in E. coli cells and further purified with Ni–NTA Sepharose and Phenyl Sepharose. It was then conjugated with DM1, and the conjugated product SCF-DM1 was evaluated using in vitro cell-based assays and in vivo xenograft mouse model.

Results

SCF-DM1 was effective in inhibiting imatinib-sensitive and -resistant GIST cell lines and primary tumor cells, with IC50 values of < 30 nM. It induced apoptosis and cell cycle arrest in GIST cells. In xenograft mouse model, SCF-DM1 showed favorable efficacy and safety profiles.

Conclusions

rhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.
Appendix
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Literature
1.
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.PubMedCrossRef
2.
Rubin BP, Blanke Cd Fau - Demetri GD, Demetri Gd Fau - Dematteo RP, Dematteo Rp Fau - Fletcher CDM, Fletcher Cd Fau - Goldblum JR, Goldblum Jr Fau - Lasota J, Lasota J Fau - Lazar A, Lazar A Fau - Maki RG, Maki Rg Fau - Miettinen M, Miettinen M Fau - Noffsinger A et al: Protocol for the examination of specimens from patients with gastrointestinal stromal tumor. (1543–2165 (Electronic)).
3.
Fletcher CDM, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33(5):459–65.PubMedCrossRef
4.
Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23(2):70–83.PubMedCrossRef
5.
Patel N, Benipal B: Incidence of gastrointestinal stromal tumors in the United States from 2001–2015: a United States cancer statistics analysis of 50 states. (2168–8184 (Print)).
6.
Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds): SEER Cancer Statistics Review, 1975–2018. In. Edited by National Cancer Institute. Bethesda M; 2021.
7.
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen C-J, Joseph N, Singer S, Griffith DJ, Haley A, Town A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.PubMedCrossRef
8.
Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloid leukemia: therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020;111(2):312–22.PubMedCrossRef
9.
Cannarile MA, Weisser M, Jacob W, Jegg A-M, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017;5(1):53.PubMedPubMedCentralCrossRef
10.
Pauls K, Merkelbach-Bruse S, Thal D, Büttner R, Wardelmann E. PDGFRα- and c-kit-mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features. Histopathology. 2005;46(2):166–75.PubMedCrossRef
11.
Szucs Z, Thway K, Fisher C, Bulusu R, Constantinidou A, Benson C. Graaf WTvd, Jones RL: Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol. 2017;13(1):93–107.PubMedCrossRef
12.
Hemming ML, Heinrich MC, Bauer S, George S. Translational insights into gastrointestinal stromal tumor and current clinical advances. Ann Oncol. 2018;29(10):2037–45.PubMedCrossRef
13.
Corless CL, Ballman KV, Antonescu CR, Kolesnikova V, Maki RG, Pisters PWT, Blackstein ME, Blanke CD, Demetri GD, Heinrich MC, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014;32(15):1563–70.PubMedPubMedCentralCrossRef
14.
Joensuu H, Wardelmann E, Sihto H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D, Cameron S, Hohenberger P, et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial. JAMA Oncol. 2017;3(5):602–9.PubMedPubMedCentralCrossRef
15.
Joensuu H, Rutkowski P, Nishida T, Steigen SE, Brabec P, Plank L, Nilsson B, Braconi C, Bordoni A, Magnusson MK, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33(6):634–42.PubMedCrossRef
16.
Abrams T, Connor A, Fanton C, Cohen SB, Huber T, Miller K, Hong EE, Niu X, Kline J, Ison-Dugenny M, et al. Preclinical antitumor activity of a novel anti–c-KIT antibody–drug conjugate against mutant and wild-type c-KIT–positive solid tumors. Clin Cancer Res. 2018;24(17):4297–308.PubMedCrossRef
17.
Kim J-O, Kim K-H, Baek EJ, Park B, So MK, Ko BJ, Ko H-J, Park SG. A novel anti-c-Kit antibody–drug conjugate to treat wild-type and activating-mutant c-Kit-positive tumors. Mol Oncol. 2022;16(6):1290–308.PubMedCrossRef
18.
Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, Jordan MA. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9(10):2689–99.PubMedPubMedCentralCrossRef
19.
Cassady JM, Chan KK, Floss HG, Leistner E: Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo). 2004;52(1):1–26.
20.
Joubert N, Beck A, Dumontet C, Denevault-Sabourin C. Antibody–drug conjugates: the last decade. Pharmaceuticals. 2020;13(9):245.PubMedCentralCrossRef
21.
Lambert JM, Chari RVJ. Ado-trastuzumab Emtansine (T-DM1): an antibody–drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014;57(16):6949–64.PubMedCrossRef
22.
Zhang D, Guo Y, Zhao Y, Yu L, Chang Z, Pei H, Huang J, Chen C, Xue H, Xu X, et al. Expression of a recombinant FLT3 ligand and its emtansine conjugate as a therapeutic candidate against acute myeloid leukemia cells with FLT3 expression. Microb Cell Fact. 2021;20(1):67.PubMedPubMedCentralCrossRef
23.
Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, Straus D, Acosta M, Negro-Vilar A. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(11):1870–7.PubMedCrossRef
24.
Jiang X, Gurel O, Mendiaz EA, Stearns GW, Clogston CL, Lu HS, Osslund TD, Syed RS, Langley KE, Hendrickson WA. Structure of the active core of human stem cell factor and analysis of binding to its receptor kit. EMBO J. 2000;19(13):3192–203.PubMedPubMedCentralCrossRef
25.
Haglund K, Dikic I. The role of ubiquitylation in receptor endocytosis and endosomal sorting. J Cell Sci. 2012;125(2):265–75.PubMedCrossRef
26.
Blay J-Y, Kang Y-K, Nishida T, von Mehren M. Gastrointestinal stromal tumours. Nat Rev Dis Primers. 2021;7(1):22.PubMedCrossRef
27.
Tilayov T, Hingaly T, Greenshpan Y, Cohen S, Akabayov B, Gazit R, Papo N. Engineering stem cell factor ligands with different c-Kit agonistic potencies. Molecules. 2020;25(20):4850.PubMedCentralCrossRef
28.
Dahlen DD, Lin NL, Liu Y-C, Broudy VC. Soluble c-kit receptor blocks stem cell factor bioactivity in vitro. Leuk Res. 2001;25(5):413–21.PubMedCrossRef
29.
Choudhary S, Pardo A, Rosinke R, Batra JK, Barth S, Verma RS. Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins. Appl Microbiol Biotechnol. 2016;100(1):263–77.PubMedCrossRef
30.
Studier FW. Protein production by auto-induction in high-density shaking cultures. Protein Expr Purif. 2005;41(1):207–34.PubMedCrossRef
31.
Guzmán-Verduzco L-M, Kupersztoch YM. Export and processing analysis of a fusion between the extracellular heat-stable enterotoxin and the periplasmic B subunit of the heat-labile enterotoxin in Escherichia coli. Mol Microbiol. 1990;4(2):253–64.PubMedCrossRef
32.
Henze J, Mühlenberg T, Simon S, Grabellus F, Rubin B, Taeger G, Schuler M, Treckmann J, Debiec-Rychter M, Taguchi T, et al. p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors. PLoS ONE. 2012;7(5):e37776–e37776.PubMedPubMedCentralCrossRef
33.
Chen Y, Guo Y, Zhao W, Tina Ho WT, Fu X, Zhao ZJ. Identification of an orally available compound with potent and broad FLT3 inhibition activity. Oncogene. 2016;35(23):2971–8.PubMedCrossRef
34.
35.
36.
Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, Leversha MA, Jeffrey PD, Desantis D, Singer S, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11(11):4182–90.PubMedCrossRef
37.
Oliver TG, Meylan E, Chang GP, Xue W, Burke JR, Humpton TJ, Hubbard D, Bhutkar A, Jacks T. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell. 2011;43(1):57–71.PubMedPubMedCentralCrossRef
38.
Pochampally R, Fodera B, Chen L, Shao W, Levine EA, Chen J. A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells. Oncogene. 1998;17(20):2629–36.PubMedCrossRef
39.
Widdison W, Wilhelm S, Veale K, Costoplus J, Jones G, Audette C, Leece B, Bartle L, Kovtun Y, Chari R: Metabolites of antibody-maytansinoid conjugates: characteristics and in vitro potencies. Mol Pharm. 2015;12(6):1762–73.
40.
Riss T, Moravec R, Niles A, Benink H. Cell viability assays. Assay Guid Man. 2013.
41.
Houen G. Therapeutic antibodiestherapeutic antibodies: an overview. In: Houen G, editor. Therapeutic Antibodies: Methods and Protocols. edn. New York, NY: Springer US; 2022. p. 1–25.CrossRef
42.
43.
Doody JF, Wang Y, Patel SN, Joynes C, Lee SP, Gerlak J, Rolser RL, Li Y, Steiner P, Bassi R, et al. Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non–small cell lung cancers. Mol Cancer Ther. 2007;6(10):2642–51.PubMedCrossRef
44.
Li Y, Li H, Wang M-N, Lu D, Bassi R, Wu Y, Zhang H, Balderes P, Ludwig DL, Pytowski B, et al. Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody. Blood. 2004;104(4):1137–44.PubMedCrossRef
45.
Sanford D, Blum WG, Ravandi F, Klisovic RB, Borthakur G, Walker AR, Garcia-Manero G, Marcucci G, Wierda WG, Whitman SP, et al. Efficacy and safety of an anti-FLT3 antibody (LY3012218) in patients with relapsed acute myeloid leukemia. J Clin Oncol. 2015;33(15_suppl):7059–7059.CrossRef
46.
Shih LB, Lu H, Xuan H, Goldenberg DM. Internalization and intracellular processing of an anti B-cell lymphoma monoclonal antibody, ll2. Int J Cancer. 1994;56(4):538–45.PubMedCrossRef
47.
Lim SH, Vaughan AT, Ashton-Key M, Williams EL, Dixon SV, Chan HTC, Beers SA, French RR, Cox KL, Davies AJ, et al. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood. 2011;118(9):2530–40.PubMedCrossRef
48.
Beum PV, Peek EM, Lindorfer MA, Beurskens FJ, Engelberts PJ, Parren PWHI, van de Winkel JGJ, Taylor RP. Loss of CD20 and bound CD20 antibody from opsonized B Cells occurs more rapidly because of trogocytosis mediated by Fc receptor-expressing effector cells than direct internalization by the B cells. J Immunol. 2011;187(6):3438–47.PubMedCrossRef
49.
Chang RB, Beatty GL. The interplay between innate and adaptive immunity in cancer shapes the productivity of cancer immunosurveillance. J Leukoc Biol. 2020;108(1):363–76.PubMedCrossRef
50.
Lebegge E, Arnouk SM, Bardet PMR, Kiss M, Raes G, Van Ginderachter JA. Innate immune defense mechanisms by myeloid cells that hamper cancer immunotherapy. Front Immunol. 2020;11:1395–1395.PubMedPubMedCentralCrossRef
51.
Yoon H, Tang C-M, Banerjee S, Delgado AL, Yebra M, Davis J, Sicklick JK. TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor. Oncogenesis. 2021;10(2):13–13.PubMedPubMedCentralCrossRef
52.
53.
Erben U, Thiel E, Notter M. Differential effects of a stem cell factor-immunoglobulin fusion protein on malignant and normal hematopoietic cells. Can Res. 1999;59(12):2924–30.
Metadata
Title
Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor
Authors
Dengyang Zhang
Chunxiao He
Yao Guo
Jianfeng Li
Bo Li
Yuming Zhao
Liuting Yu
Zhiguang Chang
Hanzhong Pei
Ming Yang
Na Li
Qi Zhang
Yulong He
Yihang Pan
Zhizhuang Joe Zhao
Changhua Zhang
Yun Chen
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02465-3

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