RN486 / Roche - LARVOL DELTA

RN486, a Bruton's Tyrosine Kinase inhibitor, antagonizes multidrug resistance in ABCG2-overexpressing cancer cells. (PubMed, J Transl Int Med) - "Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. Our studies propose that RN486 can antagonize ABCG2-mediated MDR in cancer cells via down-regulating the expression level of ABCG2 protein, reducing ATPase activity of ABCG2 transporter, and inhibiting the transporting function. RN486 could be potentially used in conjunction with chemotherapy to alleviate MDR mediated by ABCG2 in cancer."

Journal • Oncology • ABCB1 • ABCG2

NOVEL SPLICE-SITE MUTATION IN PLCG2 ASSOCIATED WITH RESISTANCE TO BTK INHIBITORS (EHA 2023) - " Among the multiple parallel lines of REC-1 cells where resistance to the covalent BTKi: ibrutinib and tirabrutinib, and the non-covalent BTKi: nemtabrutinib, pirtobrutinib, vecabrutinib, fenebrutinib and RN-486 was generated, a novel PLCG2 c.2236-1G>T mutation at the splice site was observed in 2 of 3 tirabrutinib resistant lines with variant allele frequencies (VAF) of 42% and 44%, respectively. Here, we identified a novel PLCG2 splice-site mutation in BTKi resistant REC-1 cells, which led to the deletion of exon 21, most likely impairing the auto-inhibitory regulation of the enzyme and increasing lipase activity of PLCγ2. Similar to other known PLCγ2 mutants, the novel Δ21 PLCγ2 mutant showed resistance to all BTKi tested, due toBTK independent activation of BCR signaling. Our study highlights the importance of sequencing splice sites of PLCG2 in the context of patients who progress under BTKi-based treatments."

Chronic Lymphocytic Leukemia • Oncology • NF-κβ • PLCG2

Novel BTK Mutations Conferring Resistance to Non-Covalent BTK Inhibitors and Alternative Treatment Strategy (ASH 2022) - "Here,we generated and comprehensively characterized BTK and PLCG2 mutations conferring resistance to ibrutinib and five different non-covalent BTKi namely pirtobrutinib (LOXO-305), vecabrutinib (SNS-062), nemtabrutinib (ARQ-531), fenebrutinib (GDC-0853), and RN-486. We also found that cells harboring these novel BTK mutations showed differential sensitivity to the covalent vs. non-covalent BTKi. We further demonstrate the potential of venetoclax as follow up treatment upon resistance to non-covalent BTKi."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • PLCG2

Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. (PubMed, Front Immunol) - "Covalently binding compounds, such as ibrutinib, acalabrutinib and zanubrutinib, are discussed along with non-covalent inhibitors fenebrutinib and RN486. The focus of this review is on structure-function relationships."

Journal • Review • Hematological Malignancies • Immunology • Inflammation • Oncology

Bruton's Tyrosine Kinase (BTK) Inhibitor RN486 Overcomes ABCB1-Mediated Multidrug Resistance in Cancer Cells. (PubMed, Front Cell Dev Biol) - "Previous, we uncovered that the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is a potent reversal agent to overcomes paclitaxel resistance in ABCB1-overexpressing cells and tumors...We found that RN486 significantly increased the efficacy of paclitaxel and doxorubicin in both drug-selected carcinoma cells and transfected cells overexpressing ABCB1...Moreover, an interaction between RN486 with ABCB1 substrate-binding and inhibitor binding sites was verified by in silico docking simulation. The results from our study suggest that RN486 could be a reversal agent and could be used in the novel combination therapy with other antineoplastic drugs to conquer MDR-mediated by ABCB1 transporter in clinics."

Journal • Oncology • ABCB1

p65BTK is a novel potential actionable target in KRAS-mutated/EGFR-wild type lung adenocarcinoma. (PubMed, J Exp Clin Cancer Res) - "p65BTK results as an emerging actionable target in non-smoking EGFR-wt AdC, also at advanced stages of disease. Notably, these patients are not eligible for EGFR-TKIs-based therapy due to a lack of EGFR mutation. The combination of BTK-TKIs with EGFR-TKIs is cytotoxic for EGFR-wt/KRAS-mutant/p53-null tumors and BTK-TKIs re-sensitizes drug-resistant NSCLC to SOC chemotherapy. Therefore, our data suggest that adding BTK-TKIs to SOC chemotherapy and EGFR-targeted therapy may open new avenues for clinical trials in currently untreatable NSCLC."

Biomarker • Journal