Enhanced Sensitivity of Idelalisib and Ibrutinib-Resistant Cell Lines to Anti-CD38 Antibodies

Eva-Laure, Matera; Fouret, Julien; Baulu, Estelle; Perrial, Emeline; Zineb, Bousfiha; Chettab, Kamel; Jordheim, Lars Petter; Dumontet, Charles

doi:10.26502/jcsct.5079052

Cited by 2 publications

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“…In accordance with our results, DLBCL preclinical models with acquired resistance to idelalisib exhibit decreased sensitivity to BTK inhibitors, and ibrutinib-resistant models (driven by BTK or TNFAIP3 mutations) lose response to other downstream BCR inhibitors, including idelalisib (9,15). Hence, the biological mechanisms observed for idelalisib can be extended to additional agents and new therapeutic strategies should be developed to escape acquired resistance to downstream B cell receptor targeted agents.…”

Section: Discussionsupporting

confidence: 91%

“…However, single agent treatments is often associated with limited success in achieving long-lasting complete responses, suggesting the need for combination therapies (6). The identification of the mechanisms underlying either primary or secondary resistance to signaling inhibitors (5,(7)(8)(9)(10)(11)(12)(13)(14)(15) provides useful information to optimize the use of the agents. Here, starting from a marginal zone lymphoma (MZL) cell line kept under prolonged exposure to the PI3Kd inhibitor idelalisib, we demonstrate that resistance to BTK and PI3K inhibitors can be sustained in various B cell lymphoid neoplasms by the overexpression of ERBB4 and its ligands and targeted pharmacological interventions can restore sensitivity to the small molecules.…”

Section: Introductionmentioning

confidence: 99%

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ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

Arribas

Napoli

Cascione

et al. 2023

Preprint

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BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead as single agents to long-lasting complete remission is rather limited especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors and that targeted pharmacological interventions can restore sensitivity to the small molecules. We started from a marginal zone lymphoma (MZL) 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 pharmacological 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 anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK and PI3K inhibitors in parental cells but also 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. Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were shown to be expressed in clinical samples, further extending the findings of the study. In conclusions, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors and treatments that appear to overcome it.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

Arribas

Napoli

Cascione

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

Arribas,

Napoli,

Cascione

et al. 2023

Molecular Cancer Therapeutics

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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.

show abstract

Enhanced Sensitivity of Idelalisib and Ibrutinib-Resistant Cell Lines to Anti-CD38 Antibodies

Cited by 2 publications

References 0 publications

ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

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