Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody-Drug Conjugate.
Animals
Antineoplastic Agents
/ pharmacokinetics
Cell Line, Tumor
/ drug effects
Drug Resistance, Neoplasm
Gastrointestinal Neoplasms
/ drug therapy
Gastrointestinal Stromal Tumors
/ drug therapy
Haplorhini
Humans
Immunoconjugates
/ pharmacokinetics
Japan
Rats
Receptors, CCR
/ metabolism
United States
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
07
10
2020
revised:
18
01
2021
accepted:
10
02
2021
pubmed:
14
2
2021
medline:
19
2
2022
entrez:
13
2
2021
Statut:
ppublish
Résumé
Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein-coupled receptor 20 (GPR20) as a novel non-tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression-dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. SIGNIFICANCE: GPR20 is selectively expressed in GIST across all treatment lines, regardless of
Identifiants
pubmed: 33579785
pii: 2159-8290.CD-20-1434
doi: 10.1158/2159-8290.CD-20-1434
doi:
Substances chimiques
Antineoplastic Agents
0
Immunoconjugates
0
Receptors, CCR
0
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1508-1523Informations de copyright
©2021 American Association for Cancer Research.
Références
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865–78.
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.
von Mehren M, Joensuu H. Gastrointestinal stromal tumors. J Clin Oncol. 2018;36:136–43.
Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016;2:922–8.
Jahn SW, Liegl-Atzwanger B. Wild-type GIST: a comprehensive review. memo (Mag Eur Med Oncol). 2014;7:34–8.
Nannini M, Urbini M, Astolfi A, Biasco G, Pantaleo MA. The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). J Transl Med. 2017;15:113.
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–38.
Demetri GD, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.
Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8:S1–41.
Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74.
Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9.
Avapritinib approved for GIST subgroup. Cancer Discov. 2020;10:334.
Allander SV, Nupponen NN, Ringnér M, Hostetter G, Maher GW, Goldberger N, et al. Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile. Cancer Res. 2001;61:8624–8.
Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10:3282–90.
Hase M, Yokomizo T, Shimizu T, Nakamura M. Characterization of an orphan G protein-coupled receptor, GPR20, that constitutively activates Gi proteins. J Biol Chem. 2008;283:12747–55.
Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010;467:849–53.
Ran L, Chen Y, Sher J, Wong EWP, Murphy D, Zhang JQ, et al. FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor. Cancer Discov. 2018;8:234–51.
Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37.
Parslow A, Parakh S, Lee F-T, Gan H, Scott A. Antibody–drug conjugates for cancer therapy. Biomedicines. 2016;4:14.
Ogitani Y, Abe Y, Iguchi T, Yamaguchi J, Terauchi T, Kitamura M, et al. Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology. Bioorganic Med Chem Lett. 2016;26:5069–72.
Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K, et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorganic Med Chem Lett. 2016;26:1542–5.
Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull. 2019;67:173–85.
Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6:789–802.
Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22:5097–108.
Shiose Y, Ochi Y, Kuga H, Yamashita F, Hashida M. Relationship between drug release of DE-310, macromolecular prodrug of DX-8951f, and cathepsins activity in several tumors. Biol Pharm Bull. 2007;30:2365–70.
Mohamed MM, Sloane BF. Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer. 2006;6:764–75.
Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18:1512–22.
Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107:1039–46.
Hashimoto Y, Koyama K, Kamai Y, Hirotani K, Ogitani Y, Zembutsu A, et al. A novel HER3-targeting antibody–drug conjugate, U3-1402, exhibits potent therapeutic efficacy through the delivery of cytotoxic payload by efficient internalization. Clin Cancer Res. 2019;25:7151–61.
Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610–21.
Kristensen T, Vestergaard H, Møller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagnostics. 2011;13:180–8.
Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol. 2001;21:4129–39.
Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, et al. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem. 2003;278:21767–73.
Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993;53:3976–85.
Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10:1093–5.
Nair A, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27.
Abrams T, Connor A, Fanton C, Cohen SB, Huber T, Miller K, 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;24:4297–308.
L'Italien L, Orozco O, Abrams T, Cantagallo L, Connor A, Desai J, et al. Mechanistic insights of an immunological adverse event induced by an anti-KIT antibody drug conjugate and mitigation strategies. Clin Cancer Res. 2018;24:3465–74.