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Ref Type | Journal Article | ||||||||||||
PMID | (36661329) | ||||||||||||
Authors | Qi J, Endres S, Yosifov DY, Tausch E, Dheenadayalan RP, Gao X, Müller A, Schneider C, Mertens D, Gierschik P, Wist M, Jebaraj BMC, Stilgenbauer S | ||||||||||||
Title | Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors. | ||||||||||||
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Abstract Text |
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 |
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BTK | D539H | missense | loss of function | BTK D539H lies within the protein kinase domain of the Btk protein (UniProt.org). D539H results in loss of kinase activity and reduced Btk and Plcg2 phosphorylation, increased Akt phosphorylation, and a greater sustained calcium influx upon IgM stimulation, and demonstrates resistance to BTK inhibitors in culture (PMID: 36661329). | Y |
BTK | G409R | missense | loss of function | BTK G409R lies within the protein kinase domain of the Btk protein (UniProt.org). G409R results in loss of kinase activity and reduced Btk and Plcg2 phosphorylation, increased Akt phosphorylation, and a greater sustained calcium influx upon IgM stimulation, and demonstrates resistance to BTK inhibitors in culture (PMID: 36661329). | Y |
BTK | G480R | missense | loss of function | BTK G480R lies within the protein kinase domain of the Btk protein (UniProt.org). G480R results in loss of kinase activity and reduced Btk and Plcg2 phosphorylation, increased Akt phosphorylation, and a greater sustained calcium influx upon IgM stimulation, and demonstrates resistance to BTK inhibitors in culture (PMID: 36661329). | Y |
BTK | L528S | missense | loss of function | BTK L528S lies within the protein kinase domain of the Btk protein (UniProt.org). L528S results in loss of kinase activity and reduced Btk and Plcg2 phosphorylation, increased Akt phosphorylation, and a greater sustained calcium influx upon IgM stimulation, and demonstrates resistance to BTK inhibitors in culture (PMID: 36661329). | Y |
BTK | V416L | missense | unknown | BTK V416L lies within the protein kinase domain of the Btk protein (UniProt.org). V416L results in decreased Btk and Plcg2 phosphorylation and increased calcium ion flux but retains Akt and Erk phosphorylation and demonstrates resistance to BTK inhibitors in culture (PMID: 35196427, PMID: 36661329), 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 |
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BTK D539H | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK D539H in culture (PMID: 36661329). | 36661329 |
BTK G480R | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK G480R in culture (PMID: 36661329). | 36661329 |
BTK G409R | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK G409R in culture (PMID: 36661329). | 36661329 |
BTK A428D | mantle cell lymphoma | resistant | Pirtobrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Jaypirca (pirtobrutinib) after prolonged exposure in culture, and was subsequently found to have acquired BTK A428D (PMID: 36661329). | 36661329 |
BTK A428D | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK A428D in culture (PMID: 36661329). | 36661329 |
BTK C481F | mantle cell lymphoma | resistant | Ibrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Imbruvica (ibrutinib) after prolonged exposure in culture, and was subsequently found to have acquired BTK C481F (PMID: 36661329). | 36661329 |
BTK L528S | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK L528S in culture (PMID: 36661329). | 36661329 |
BTK G480R | mantle cell lymphoma | resistant | Fenebrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Fenebrutinib (GDC-0853) after prolonged exposure in culture, and was subsequently found to have acquired BTK G480R (PMID: 36661329). | 36661329 |
BTK V416L | mantle cell lymphoma | resistant | RN486 | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to RN486 after prolonged exposure in culture, and was subsequently found to have acquired BTK V416L (PMID: 36661329). | 36661329 |
BTK D539H | mantle cell lymphoma | resistant | Fenebrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Fenebrutinib (GDC-0853) after prolonged exposure in culture, and was subsequently found to have acquired BTK D539H (PMID: 36661329). | 36661329 |
BTK C481F | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK C481F in culture (PMID: 36661329). | 36661329 |
BTK G480R | mantle cell lymphoma | resistant | RN486 | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to RN486 after prolonged exposure in culture, and was subsequently found to have acquired BTK G480R (PMID: 36661329). | 36661329 |
BTK V416L | mantle cell lymphoma | sensitive | ARQ 531 | Preclinical - Cell culture | Actionable | In a preclinical study, ARQ 531 inhibited viability of a mantle cell lymphoma cell line harboring BTK V416L in culture (PMID: 36661329). | 36661329 |
BTK G409R | mantle cell lymphoma | resistant | Vecabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Vecabrutinib (SNS-062) after prolonged exposure in culture, and was subsequently found to have acquired BTK G409R (PMID: 36661329). | 36661329 |
BTK L528S | mantle cell lymphoma | resistant | Fenebrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a mantle cell lymphoma cell line developed resistance to Fenebrutinib (GDC-0853) after prolonged exposure in culture, and was subsequently found to have acquired BTK L528S (PMID: 36661329). | 36661329 |