PI3Kδ activation, IL6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas.

Autor:	Arribas AJ; Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland., Napoli S; Institute of Oncology Research, Bellinzona, Switzerland., Gaudio E; Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland., Herbaux C; CHU Montpellier UMR5535, Montpellier, France., Cannas E; 1 Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland, Bellinzona, Switzerland., Tarantelli C; Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland., Bordone Pittau R; IOSI Oncology Institute of Southern Switzerland., Cascione L; IOR - Institute of Oncology Research, Bellinzona, Switzerland., Munz N; Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland., Aresu L; University of Turin, Grugliasco, Italy., Sgrignani J; Institute of Research in Biomedicine, Bellinzona, Switzerland., Rinaldi A; Institute of Oncology Research, Bellinzona, Switzerland., Kwee I; BigOmics Analytics SA, Lugano, Switzerland., Rossi D; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Cavalli A; Università della Svizzera italiana, Bellonzona, Switzerland., Zucca E; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland., Stussi G, Stathis A; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzoona, Switzerland., Sloss C; ImmunoGen, Inc., Davids MS; Dana-Farber Cancer Institute, Boston, Massachusetts, United States., Bertoni F; Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Oct 07. Date of Electronic Publication: 2024 Oct 07.
DOI:	10.1182/bloodadvances.2023012291
Abstrakt:	CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562, IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in lymphoma patients. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of IL6 and related transcripts. Recombinant IL6 led to resistance. Anti-IL6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved the cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
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