journal contribution
posted on 2024-03-04, 19:42 authored by Alberto J. Arribas, Sara Napoli, Luciano Cascione, Laura Barnabei, Giulio Sartori, Eleonora Cannas, Eugenio Gaudio, Chiara Tarantelli, Afua A. Mensah, Filippo Spriano, Antonella Zucchetto, Francesca M. Rossi, Andrea Rinaldi, Manuel Castro de Moura, Sandra Jovic, Roberta Bordone Pittau, Anastasios Stathis, Georg Stussi, Valter Gattei, Jennifer R. Brown, Manel Esteller, Emanuele Zucca, Davide Rossi, Francesco Bertoni Factors associated with resistance to idelalisib in cell lines are expressed in clinical specimens. Expression levels of genes related to idelalisib resistance were studied across different subtypes of B cell lymphoma: (A) n=48 (5), (B) n=80 (6). B-CLL: chronic lymphocytic leukemia, B.FL: follicular lymphoma, LBNH: non-specified non-Hodgkin B cell lymphoma, MALT: MZL of the mucosa associated tissue, MCL: Mantle cell lymphoma, NMZL: nodal marginal zone lymphoma, SMZL: splenic marginal zone lymphoma. Expression levels of genes related to idelalisib resistance were studied across the subtypes of diffuse large B cell lymphoma (DLBCL, two series: (C) n=181 and (D) n=223 from GSE10846 (7). ABC: activated B cell like DLBCL, GCB: germinal center B cell like DLBCL, type3: type3 DLBCL. Red for highly expressed gene in B cells (CD79A), blue for not expressed gene in B cells (IGFBP1), black for the gene of interest. (E) Gene set enrichment analyses comparing resistant versus parental for the top-200 genes positively correlated genes with HBEGF in SMZL clinical specimens (6). NES: normalized enrichment score, p-val: nominal p-value, FDR: false discovery rate.
Funding
Swiss National Science Foundation (SNSF)
Nelia and Amadeo Foundation
NIH
History
ARTICLE ABSTRACT
BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole-exome sequencing, and pharmacologic screening, which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the antitumor activity of various BTK/PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK/PI3K inhibitors in parental cells and in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. An epigenetic reprogramming sustained the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were also shown to be expressed in clinical specimens. In conclusion, we showed that the overexpression of ERBB4 and its ligands represents a novel mechanism of resistance for lymphoma cells to bypass the antitumor activity of BTK and PI3K inhibitors and that targeted pharmacologic interventions can restore sensitivity to the small molecules.
