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Ref Type Journal Article
PMID (38052765)
Authors Arribas AJ, Napoli S, Cascione L, Barnabei L, Sartori G, Cannas E, Gaudio E, Tarantelli C, Mensah AA, Spriano F, Zucchetto A, Rossi FM, Rinaldi A, Castro de Moura M, Jovic S, Bordone Pittau R, Stathis A, Stussi G, Gattei V, Brown JR, Esteller M, Zucca E, Rossi D, Bertoni F
Title ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 23 3 2024 Mar 04 368-380 Mol Cancer Ther
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 over exp marginal zone lymphoma resistant Idelalisib + Rituximab Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to combination treatment with Rituxan (rituximab) and Zydelig (idelalisib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Copanlisib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Aliqopa (copanlisib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Umbralisib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Ukoniq (umbralisib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Idelalisib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line was found to have ERBB4 overexpression following acquired resistance to Zydelig (idealisib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Duvelisib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Copiktra (duvelisib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma sensitive Idelalisib + Lapatinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Tykerb (lapatinib) restored sensitivity to Zydelig (idealisib) and led to synergistic inhibition of viability in a marginal zone lymphoma cell line with ERBB4 overexpression in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Acalabrutinib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Calquence (acalabrutinib) in culture (PMID: 38052765). 38052765
ERBB4 over exp marginal zone lymphoma resistant Zanubrutinib Preclinical - Cell culture Actionable In a preclinical study, a marginal zone lymphoma cell line with ERBB4 overexpression demonstrated resistance to Brukinsa (zanubrutinib) in culture (PMID: 38052765). 38052765