Bortezomib Promotes the TRAIL-mediated Killing of Resistant Rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 Cells Via DR5 Upregulation

Overview

Journal Mol Ther Oncol

Date 2024 May 6

PMID 38706988

Authors

Catrin Heim

Leonie Hartig

Nadine Weinelt

Laura M Moser

Emilia Salzmann-Manrique

Michael Merker

Winfried S Wels

Torsten Tonn

Peter Bader

Jan-Henning Klusmann

Sjoerd J L van Wijk

Eva Rettinger

Affiliations

Soon will be listed here.

Abstract

Treatment resistance and immune escape are hallmarks of metastatic rhabdomyosarcoma (RMS), underscoring the urgent medical need for therapeutic agents against this disease entity as a key challenge in pediatric oncology. Chimeric antigen receptor (CAR)-based immunotherapies, such as the ErbB2 (Her2)-CAR-engineered natural killer (NK) cell line NK-92/5.28.z, provide antitumor cytotoxicity primarily through CAR-mediated cytotoxic granule release and thereafter-even in cases with low surface antigen expression or tumor escape-by triggering intrinsic NK cell-mediated apoptosis induction via additional ligand/receptors. In this study, we showed that bortezomib increased susceptibility toward apoptosis in clinically relevant RMS cell lines RH30 and RH41, and patient-derived RMS tumor organoid RMS335, by upregulation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor DR5 in these metastatic, relapsed/refractory (r/r) RMS tumors. Subsequent administration of NK-92/5.28.z cells significantly enhanced antitumor activity . Applying recombinant TRAIL instead of NK-92/5.28.z cells confirmed that the synergistic antitumor effects of the combination treatment were mediated via TRAIL. Western blot analyses indicated that the combination treatment with bortezomib and NK-92/5.28.z cells increased apoptosis by interacting with the nuclear factor κB, JNK, and caspase pathways. Overall, bortezomib pretreatment can sensitize r/r RMS tumors to CAR- and, by upregulating DR5, TRAIL-mediated cytotoxicity of NK-92/5.28.z cells.

References

Hinson A, Jones R, Crose L, Belyea B, Barr F, Linardic C . Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls. Front Oncol. 2013; 3:183. PMC: 3713458. DOI: 10.3389/fonc.2013.00183. View

Gurria J, Dasgupta R . Rhabdomyosarcoma and Extraosseous Ewing Sarcoma. Children (Basel). 2018; 5(12). PMC: 6306718. DOI: 10.3390/children5120165. View

Burger M, Zhang C, Harter P, Romanski A, Strassheimer F, Senft C . CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. Front Immunol. 2019; 10:2683. PMC: 6868035. DOI: 10.3389/fimmu.2019.02683. View

Chen D, Frezza M, Schmitt S, Kanwar J, Dou Q . Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011; 11(3):239-53. PMC: 3306611. DOI: 10.2174/156800911794519752. View

Hellwig C, Delgado M, Skoko J, Dyck L, Hanna C, Wentges A . Proteasome inhibition triggers the formation of TRAIL receptor 2 platforms for caspase-8 activation that accumulate in the cytosol. Cell Death Differ. 2021; 29(1):147-155. PMC: 8738721. DOI: 10.1038/s41418-021-00843-7. View

Pan K, Farrukh H, Chittepu V, Xu H, Pan C, Zhu Z . CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022; 41(1):119. PMC: 8969382. DOI: 10.1186/s13046-022-02327-z. View

Prager I, Watzl C . Mechanisms of natural killer cell-mediated cellular cytotoxicity. J Leukoc Biol. 2019; 105(6):1319-1329. DOI: 10.1002/JLB.MR0718-269R. View

Schonfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M . Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther. 2014; 23(2):330-8. PMC: 4445620. DOI: 10.1038/mt.2014.219. View

Koschny R, Ganten T, Sykora J, Haas T, Sprick M, Kolb A . TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology. 2007; 45(3):649-58. DOI: 10.1002/hep.21555. View

10.

Xia L, Tan S, Zhou Y, Lin J, Wang H, Oyang L . Role of the NFκB-signaling pathway in cancer. Onco Targets Ther. 2018; 11:2063-2073. PMC: 5905465. DOI: 10.2147/OTT.S161109. View

11.

Takeda K, Smyth M, Cretney E, Hayakawa Y, Kayagaki N, Yagita H . Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med. 2002; 195(2):161-9. PMC: 2193611. DOI: 10.1084/jem.20011171. View

12.

Srivastava R . TRAIL/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia. 2002; 3(6):535-46. PMC: 1506567. DOI: 10.1038/sj.neo.7900203. View

13.

Baou M, Kohlhaas S, Butterworth M, Vogler M, Dinsdale D, Walewska R . Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells. Haematologica. 2010; 95(9):1510-8. PMC: 2930952. DOI: 10.3324/haematol.2010.022368. View

14.

Koschny R, Holland H, Sykora J, Erdal H, Krupp W, Bauer M . Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis. J Neurooncol. 2009; 97(2):171-85. DOI: 10.1007/s11060-009-0010-6. View

15.

Teicher B, Ara G, Herbst R, Palombella V, Adams J . The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res. 1999; 5(9):2638-45. View

16.

Maki R, Kraft A, Scheu K, Yamada J, Wadler S, Antonescu C . A multicenter Phase II study of bortezomib in recurrent or metastatic sarcomas. Cancer. 2005; 103(7):1431-8. DOI: 10.1002/cncr.20968. View

17.

Saxon J, Yu H, Polosukhin V, Stathopoulos G, Gleaves L, McLoed A . p52 expression enhances lung cancer progression. Sci Rep. 2018; 8(1):6078. PMC: 5904214. DOI: 10.1038/s41598-018-24488-8. View

18.

Qureshi M, Romero M, Attar R, Javed Z, Farooqi A . TRAIL and Bortezomib: killing cancer with two stones. Asian Pac J Cancer Prev. 2015; 16(4):1671-4. DOI: 10.7314/apjcp.2015.16.4.1671. View

19.

Ames E, Hallett W, Murphy W . Sensitization of human breast cancer cells to natural killer cell-mediated cytotoxicity by proteasome inhibition. Clin Exp Immunol. 2009; 155(3):504-13. PMC: 2669527. DOI: 10.1111/j.1365-2249.2008.03818.x. View

20.

Gras Navarro A, Espedal H, Joseph J, Trachsel-Moncho L, Bahador M, Gjertsen B . Pretreatment of Glioblastoma with Bortezomib Potentiates Natural Killer Cell Cytotoxicity through TRAIL/DR5 Mediated Apoptosis and Prolongs Animal Survival. Cancers (Basel). 2019; 11(7). PMC: 6678126. DOI: 10.3390/cancers11070996. View