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| Ref Type | Journal Article | ||||||||||||
| PMID | (28178345) | ||||||||||||
| Authors | Yahiaoui A, Meadows SA, Sorensen RA, Cui ZH, Keegan KS, Brockett R, Chen G, Quéva C, Li L, Tannheimer SL | ||||||||||||
| Title | PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors. | ||||||||||||
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| Abstract Text | Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598). | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| BTK | C481F | missense | unknown | BTK C481F lies within the protein kinase domain of the Btk protein (UniProt.org). C481F confers resistance to BTK inhibitors (PMID: 25189416, PMID: 28178345, PMID: 27282255, PMID: 35639855) and results in loss of autophosphorylation (PMID: 25189416, PMID: 28178345, PMID: 27282255) and loss of kinase activity in an in vitro assay (PMID: 36183831), but maintains BCR signaling through activation of Hck in culture (PMID: 35639855), and therefore, its effect on Btk protein function is unknown. | Y |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| PTEN loss | diffuse large B-cell lymphoma | predicted - sensitive | GSK2334470 + Idelalisib | Preclinical - Cell culture | Actionable | In a preclinical study, GSK2334470 partially restored sensitivity to Zydelig (idelalisib) in diffuse large B-cell lymphoma cells harboring PTEN loss that acquired resistance to Zydelig (idelalisib), resulting in increased apoptosis in culture (PMID: 28178345). | 28178345 |
| BTK C481F | diffuse large B-cell lymphoma | resistant | Idelalisib | Preclinical - Cell culture | Actionable | In a preclinical study, diffuse large B-cell lymphoma cells that acquired resistance to Imbruvica (ibrutinib) harbored the BTK C481F mutation, and was resistant to Zydelig (idelalisib) in culture (PMID: 28178345). | 28178345 |
| PTEN loss | diffuse large B-cell lymphoma | predicted - sensitive | Idelalisib + MK2206 | Preclinical - Cell culture | Actionable | In a preclinical study, MK2206 partially restored sensitivity to Zydelig (idelalisib) in diffuse large B-cell lymphoma cells harboring PTEN loss with acquired resistance to Zydelig (idelalisib), resulting in increased apoptosis in culture (PMID: 28178345). | 28178345 |
| BTK C481F | diffuse large B-cell lymphoma | resistant | Idelalisib + Tirabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, diffuse large B-cell lymphoma cells that acquired resistance to Imbruvica (ibrutinib) harbored the BTK C481F mutation, and was resistant to Zydelig (idelalisib) and Tirabrutinib (ONO-4059) combination treatment in culture (PMID: 28178345). | 28178345 |
| BTK C481F | diffuse large B-cell lymphoma | resistant | Tirabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, diffuse large B-cell lymphoma cells that acquired resistance to Imbruvica (ibrutinib) harbored the BTK C481F mutation, and was resistant to Tirabrutinib (ONO-4059) in culture (PMID: 28178345). | 28178345 |
| BTK C481F | diffuse large B-cell lymphoma | resistant | Ibrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, the BTK C481F mutation was identified in diffuse large B-cell lymphoma cells that acquired resistance to Imbruvica (ibrutinib) in culture (PMID: 28178345). | 28178345 |