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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.
Journal Vol Issue Date Pages Journal Short Title
Blood advances 7 19 2023 Oct 10 5698-5702 Blood Adv
URL
Abstract Text

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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
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 loss of function - predicted BTK V416L lies within the protein kinase domain of the Btk protein (UniProt.org). V416L retains Akt and Erk phosphorylation in culture (PMID: 35196427, PMID: 36661329), but results in decreased Btk autophosphorylation and loss of kinase activity in culture (PMID: 38301010), decreased Btk and Plcg2 phosphorylation and increased calcium ion flux in culture, and demonstrates resistance to BTK inhibitors in culture (PMID: 35196427, PMID: 36661329), and therefore, is predicted to lead to a loss of Btk protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 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 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 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 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 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
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 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 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 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