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BIOMARKER:

BTK C481S

i
Other names: BTK, Bruton Tyrosine Kinase, Bruton Agammaglobulinemia Tyrosine Kinase, Tyrosine-Protein Kinase BTK, Bruton'S Tyrosine Kinase, B-Cell Progenitor Kinase, AGMX1, ATK, BPK, Tyrosine-Protein Kinase BTK Isoform (Lacking Exon 13 To 17), Dominant-Negative Kinase-Deficient Brutons Tyrosine Kinase, Tyrosine-Protein Kinase BTK Isoform (Lacking Exon 14), Truncated Bruton Agammaglobulinemia Tyrosine Kinase, Agammaglobulinaemia Tyrosine Kinase, Agammaglobulinemia Tyrosine Kinase, PSCTK1, IGHD3, IMD1, XLA, AT
Entrez ID:
Related biomarkers:
22d
-----NRX-0492 Degrades Wildtype and C481 Mutant BTK and Demonstrates in vivo Activity in CLL Patient Derived Xenografts. (PubMed, Blood)
In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR mediated signaling, transcriptional programs, and chemokine secretion. Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).
Preclinical • Journal
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CRBN (Cereblon)
|
BTK C481S • BTK C481
|
ibrutinib • NRX0492
1m
Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study (ASH 2022)
Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of both wild-type and ibrutinib-resistant C481S-mutated BTK. Nemtabrutinib 65 mg continued to show promising and durable antitumor activity with a manageable safety profile in a highly relapsed/refractory population who had prior therapy with novel agents.
Clinical • P1/2 data
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • BTK C481S • BTK C481
|
ibrutinib • nemtabrutinib (MK-1026)
1m
Bruton's Tyrosine Kinase (BTK) Degrader Nx-2127 Exhibits Lethal Activity and Synergy with Venetoclax and BET Protein Inhibitor Against MCL Cells Sensitive or Resistant to Covalent BTK Inhibitors (ASH 2022)
Covalent BTK inhibitors (BTKis), including ibrutinib and acalabrutinib, irreversibly bind to cysteine 481 in the kinase domain of BTK, inhibit growth, and induce loss of viability of MCL cells...In the present studies, we determined that in vitro exposure of human MCL cells, including MCL cell lines: REC1, Mino and JeKo-1, as well as patient-derived (PD) MCL cells, to NX-2127 (10 to 250 nM) for 2 to 24 hours markedly depleted BTK levels via proteasomal degradation, since co-treatment with the proteasome inhibitor carfilzomib restored BTK levels. NX-2127 but not NX-5948 treatment also degraded and depleted IKZF1 and IKZF3 levels...Co-treatment with NX-2127 (10 to 100 nM) and low nM levels of venetoclax or ABBV-744 was synergistically lethal against MCL cells (Delta synergy score above 1.0 by ZIP method). Collectively, these findings demonstrate that treatment with NX-2127 degrades and attenuates BTK and IKZF1/3 levels, as well as inhibits the downstream pro-growth and pro-survival signaling, resulting in loss of viability of MCL cells, including those resistant to covalent BTKi treatment. These findings also show promising anti-MCL activity of NX-2127-based combination with BCL2 or BET inhibitor which merits further in vivo validation.
IO biomarker
|
CCND1 (Cyclin D1) • CRBN (Cereblon) • IKZF1 (IKAROS Family Zinc Finger 1) • BIRC3 (Baculoviral IAP repeat containing 3) • TNFA (Tumor Necrosis Factor-Alpha) • CARD11 (Caspase Recruitment Domain Family Member 11) • PLCG2 (Phospholipase C Gamma 2) • IKZF3 (IKAROS Family Zinc Finger 3) • IL10 (Interleukin 10) • MAP3K14 (Mitogen-Activated Protein Kinase Kinase Kinase 14) • SOX11 (SRY-Box Transcription Factor 11)
|
BTK C481S • CARD11 mutation • BTK mutation • BTK C481 • CCND1 mutation
|
Venclexta (venetoclax) • ibrutinib • Calquence (acalabrutinib) • carfilzomib • ABBV-744 • NX-2127 • NX-5948
1m
Discovery and Preclinical Study of Novel BTK Degrader HZ-Q1060 (ASH 2022)
In the subcutaneous transplanted tumor model of OCI-ly10 mice, the tumor growth was completely inhibited by 3mg/kg of HZ-Q1060 administered orally every day for 14 days, which was equivalent to that of ibrutinib 10mg/kg... In summary, HZ-Q1060 is a potent and selective degrader of BTK with good ADME properties and in vivo efficacy, which makes it suitable for further evaluation in clinical development.
Preclinical
|
EGFR (Epidermal growth factor receptor)
|
BTK C481S
|
ibrutinib
1m
Pharmacological Profiling of Cells from Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Pirtobrutinib (ASH 2022)
We incubated peripheral blood mononuclear cells for three days with cBTKi – ibrutinib; glutathione inhibitor (also known as mtTP53 modulator) - APR-246; Bcl-2 antagonist - venetoclax; and Mcl-1 antagonist - AZD5991; as single agent and in double or triple combinations and apoptosis was assessed by flow cytometry. Patients were re-sensitized to ibrutinib after loss of C481S clone. Genomic and genetic profile along with pharmacological landscape provide precision medicine for these heavily pretreated patients whose disease is resistant to BTK inhibitors.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MCL1 (Myeloid cell leukemia 1) • PLCG2 (Phospholipase C Gamma 2)
|
TP53 mutation • ATM mutation • NOTCH1 mutation • BTK C481S • BTK C481 • TS 12
|
Venclexta (venetoclax) • ibrutinib • eprenetapopt (APR-246) • pirtobrutinib (LOXO-305) • AZD5991
1m
Pirtobrutinib Targets BTK C481S in Ibrutinib-Resistant CLL but Second-Site BTK Mutations Lead to Resistance. (PubMed, Blood Adv)
At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability and cytokine production. We employed longitudinal whole exome sequencing on two patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to non-covalent BTKi.
Journal
|
BTK (Bruton Tyrosine Kinase)
|
BTK C481S • BTK mutation
|
ibrutinib • pirtobrutinib (LOXO-305)
2ms
Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. (PubMed, Blood Adv)
UBX-382 was effective on seven out of eight known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. UBX-382 also provoked the cell-type-dependent and selective degradation of cereblon (CRBN) neo-substrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.
Preclinical • Journal
|
BTK (Bruton Tyrosine Kinase) • CRBN (Cereblon)
|
BTK C481S • BTK mutation • BTK C481
|
ibrutinib • nemtabrutinib (MK-1026)
2ms
Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations in Waldenström macroglobulinemia therapy: structural mechanistic insights on the role of fenebrutinib. (PubMed, J Mol Model)
Findings from this study, therefore, provide insights into the inhibitory mechanism of fenebrutinib at the atomistic level and reveal its high selectivity towards BTK variants. These insights could be key in designing and developing BTK mutants' inhibitors to treat Waldenström macroglobulinemia (WM).
Journal
|
BTK (Bruton Tyrosine Kinase)
|
BTK C481S • BTK mutation
|
fenebrutinib (GDC-0853)
2ms
Two-Track Virtual Screening Approach to Identify the Dual Inhibitors of Wild Type and C481S Mutant of Bruton's Tyrosine Kinase. (PubMed, J Chem Inf Model)
To increase the potential of a drug candidate, 1 was modified into 6,7-dimethoxy-N-(pyridin-3-yl)quinazolin-4-amine (12) via chemical synthesis so as to possess better physicochemical properties without loss of the biochemical potency. 12 is suggested as a new effective molecular core from which numerous druggable dual inhibitors of the wild-type BTK and the C481S mutant would be derivatized.
Journal
|
BTK (Bruton Tyrosine Kinase)
|
BTK C481S • BTK mutation
3ms
Extended Abstract: New BTKi (SOHO 2022)
It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.
IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • PLCG2 (Phospholipase C Gamma 2) • IL2 (Interleukin 2) • ITK (IL2 Inducible T Cell Kinase)
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Chr del(11q) • BTK C481S • PLCG2 mutation • BTK mutation • BTK C481
|
Venclexta (venetoclax) • ibrutinib • Rituxan (rituximab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Zydelig (idelalisib) • entospletinib (GS-9973) • Yinuokai (orelabrutinib) • pomalidomide • pirtobrutinib (LOXO-305) • Ukoniq (umbralisib) • TG-1701 • Utuxin (ublituximab) • luxeptinib (CG-806) • vecabrutinib (SNS-062) • DTRM-555 • DTRMWXHS-12 • Velexbru (tirabrutinib) • fenebrutinib (GDC-0853) • nemtabrutinib (MK-1026)
7ms
BTK GENE MUTATIONS IN RUSSIAN PATIENTS TREATED WITH IBRUTINIB: AS-PCR VERSUS NGS FOR ALLELIC LOAD ASSESSMENT (EHA 2022)
Conclusion AS-PCR protocol effective for the analysis of the BTK gene muta tions leading to an amino acid substitution at position C481 has been developed and validated. Prospective studies of low burden BTK mutations in the pathogenesis of relapse in CLL patients treated with BTK inhibitors have been started using this approach.
Clinical • Next-generation sequencing • Tumor Mutational Burden
|
TMB (Tumor Mutational Burden) • BTK (Bruton Tyrosine Kinase)
|
BTK C481S • BTK mutation • BTK C481 • BTK C481Y
|
ibrutinib
7ms
A FIRST-IN-HUMAN PHASE 1 TRIAL OF NX-2127, A FIRST-IN-CLASS ORAL BTK DEGRADER WITH IMID-LIKE ACTIVITY, IN PATIENTS WITH RELAPSED AND REFRACTORY B-CELL MALIGNANCIES (EHA 2022)
Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy...NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro...The primary endpoint are dose-limiting toxicities and maximum tolerated dose (Phase 1a), objective response (Phase 1b), and safety (Phase 1a and Phase 1b) of NX-1607...Conclusion Accrual is ongoing. Clinical trial information: NCT04830137.
Clinical • P1 data
|
CRBN (Cereblon) • IKZF1 (IKAROS Family Zinc Finger 1) • IKZF3 (IKAROS Family Zinc Finger 3)
|
BTK C481S • BTK mutation • BTK C481
|
ibrutinib • lenalidomide • NX-2127 • NX-1607
7ms
META-ANALYSIS OF LOW ALLELIC BURDEN C481 BTK-MUTATIONS CALLS FOR CAUTION IN IBRUTINIB RESISTANCE EVALUATION (EHA 2022)
Therefore, it is crucial to investigate the lower limit of detection. The meta-analysis suggests that variants below a certain threshold, here empirically 10%, may in many cases be false-positive variants, in agreement with other reports involving WES in general, introduced by erroneous base calling, PCR errors, etc. Although intriguing, it remains to elaborate whether the haploinsufficiency of BTK in males skew in the degree of ibrutinib resistance.
Retrospective data • Tumor Mutational Burden
|
TMB (Tumor Mutational Burden) • BTK (Bruton Tyrosine Kinase)
|
TMB-L • BTK C481S • BTK mutation • BTK C481
|
ibrutinib
7ms
NEMTABRUTINIB (MK-1026), A NON-COVALENT INHIBITOR OF WILD-TYPE AND C481S MUTATED BRUTON TYROSINE KINASE FOR B-CELL MALIGNANCIES: EFFICACY AND SAFETY OF THE PHASE 2 DOSE-EXPANSION BELLWAVE-001 STUDY (EHA 2022)
Conclusion Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing.
Clinical • P2 data • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • BTK (Bruton Tyrosine Kinase) • BCL6 (B-cell CLL/lymphoma 6) • PLCG2 (Phospholipase C Gamma 2)
|
BTK C481S • BTK mutation • BTK C481
|
nemtabrutinib (MK-1026)
1year
Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab. (PubMed, Blood Adv)
No patients acquired C481S BTK mutations implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.
Journal • PD(L)-1 Biomarker • Circulating tumor DNA
|
TP53 (Tumor protein P53) • BTK (Bruton Tyrosine Kinase) • PLCG2 (Phospholipase C Gamma 2)
|
TP53 mutation • BTK C481S • BTK mutation
|
Opdivo (nivolumab) • ibrutinib
1year
Nx-5948, a Selective Degrader of BTK with Activity in Preclinical Models of Hematologic and Brain Malignancies (ASH 2021)
Bruton’s tyrosine kinase (BTK) plays a key role in cell survival in B cell malignancies, and covalent inhibitors of BTK, such as ibrutinib and acalabrutinib, have proven efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenstrom’s macroglobulinemia (WM)...While some CRBN-binding drugs , such as lenalidomide and pomalidomide , promote the degradation of neo-substrate proteins, such as the transcription factors Aiolos and Ikaros, NX-5948 has been engineered to avoid Aiolos and Ikaros degradation and therefore do es not possess IMiD activity...In an intracranial TMD8 xenograft model, treatment with NX-5948 resulted in degradation of BTK in intracranial TMD8 cells, decreased intracranial tumor burden and improved survival relative to treatment with vehicle. The potent BTK degradation activity of NX-5948 and the ability of this molecule to penetrate the CNS supports its development for the treatment of B-cell malignancies, including CNS lymphoma .
Preclinical
|
CRBN (Cereblon) • IKZF1 (IKAROS Family Zinc Finger 1)
|
BTK C481S • BTK C481
|
ibrutinib • lenalidomide • Calquence (acalabrutinib) • pomalidomide • NX-5948
1year
Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study (ASH 2021)
Conclusion : MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of MK-1026 in B-cell malignancies is ongoing.
Clinical • P2 data • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • BTK (Bruton Tyrosine Kinase) • BCL6 (B-cell CLL/lymphoma 6) • PLCG2 (Phospholipase C Gamma 2)
|
BTK C481S • BTK mutation • BTK C481
|
nemtabrutinib (MK-1026)
1year
Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia. (PubMed, Blood)
Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.
Journal
|
CD8 (cluster of differentiation 8) • IL2 (Interleukin 2) • CD4 (CD4 Molecule) • ITK (IL2 Inducible T Cell Kinase)
|
BTK C481S • BTK mutation
|
Venclexta (venetoclax) • ibrutinib • vecabrutinib (SNS-062)
1year
Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL. (PubMed, Blood Adv)
The overall survival duration was slightly lower in mice expressing mutant BTK. Our cell lines and murine models mimicking ibrutinib-resistant CLL will serve as powerful tools to test reversible BTK inhibitors and novel, non-BTK-targeted therapeutics.
Preclinical • Journal
|
CD19 (CD19 Molecule) • PLCG2 (Phospholipase C Gamma 2) • FCER2 (Fc Fragment Of IgE Receptor II)
|
BTK C481S • BTK C481 • BTK C481R • BTK overexpression
|
ibrutinib
over1year
[VIRTUAL] Case Presentations – Management of the Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After BTK Inhibitor and BCL2 Inhibitor Therapy and Richter Transformation (SOHO 2021)
An example of these is pirtobrutinib (LOXO-305), which has demonstrated activity in patients previously treated with covalent BTK inhibitors, including patients resistant to covalent BTK inhibitors.3 Other reversible BTK inhibitors are also in clinical development...RT occurs in 3%–20% of CLL patients, with the ranges varying across studies.6 While the pathophysiology of RT is complex, a high percentage of patients have TP53 aberrancy and/or complex karyotype.7 Historically, chemoimmunotherapy has been used to treat RT; examples of regimens that have been reported to have activity include R-CHOP,8 hyper-CVAD,9 and OFAR (oxaliplatin, fludarabine, cytarabine, and rituximab).10 Despite the use of intensive chemotherapy, the outcomes of patients with RT have remained poor, with median survivals in the range of 4–8 months in trials of aggressive chemotherapy regimens...Novel agents being explored in RT include the checkpoint inhibitors pembrolizumab and nivolumab, the PI3K inhibitor umbralisib, and CAR-T cell therapy...Subsequent therapies have included ibrutinib; venetoclax; the combination of rituximab, bendamustine, and idelalisib; and acalabrutinib plus obinutuzumab...Subsequent treatments included chlorambucil plus obinutuzumab, venetoclax, ibrutinib, and idelalisib-rituximab. In 2019 a bone marrow examination demonstrated RT. She was then treated with dose-adjusted EPOCH-R, followed by bendamustine-rituximab, before she expired from progressive disease.
Clinical • PD(L)-1 Biomarker • IO biomarker
|
TP53 (Tumor protein P53) • PLCG2 (Phospholipase C Gamma 2)
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BTK C481S • PLCG2 mutation
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Venclexta (venetoclax) • ibrutinib • Rituxan (rituximab) • cytarabine • Gazyva (obinutuzumab) • oxaliplatin • Calquence (acalabrutinib) • Zydelig (idelalisib) • bendamustine • pirtobrutinib (LOXO-305) • Ukoniq (umbralisib) • Leukeran (chlorambucil) • fludarabine IV
over1year
Morphologic and molecular analysis of Richter syndrome in chronic lymphocytic leukaemia patients treated with ibrutinib or venetoclax. (PubMed, Pathology)
Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax.
Clinical • Journal • IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • BTK C481S • BCL2 G101V
|
Venclexta (venetoclax) • ibrutinib
over1year
Genomics of Resistance to Targeted Therapies. (PubMed, Hematol Oncol Clin North Am)
C481S mutation decreases the covalent binding affinity of ibrutinib to BTK, resulting in reversible rather than irreversible inhibition. Mutation in BCL2 (Gly101Val) decreases the affinity of BCL2 for venetoclax and confers acquired resistance in cell lines and primary patient cells. This review discusses the common mechanisms of resistance to targeted therapies in chronic lymphocytic leukemia.
Review • Journal • IO biomarker
|
BTK (Bruton Tyrosine Kinase) • PLCG2 (Phospholipase C Gamma 2)
|
BTK C481S • PLCG2 mutation • BTK mutation
|
Venclexta (venetoclax) • ibrutinib
over1year
[VIRTUAL] Mechanisms of acquired resistance in B-cell malignancies treated with the selective BTK inhibitor (BTKi), tirabrutinib (BSH 2021)
Ibrutinib inhibits migration of CLL cells towards chemokines such as CXCL12 and 13 and prevents secretion of BCR-dependent chemokines CCL3 and CCL4, suggesting that treatment inhibits homing and retention of malignant cells in their survival niches (de Gorter et al 2007, Ponader 2012), thus suggesting resistance may be mediated via alterations of cell migration and localisation (although the roles in DLBCL cell line models remain unclear). Overall, these data show that resistance to tirabrutinib is mediated by rapid and profound changes in gene expression as well as non- transcriptional mechanisms affecting BCR and chemokine receptor signalling as well as metabolic changes.
Preclinical
|
CD19 (CD19 Molecule) • BTK (Bruton Tyrosine Kinase) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • PLCG2 (Phospholipase C Gamma 2) • CD22 (CD22 Molecule) • CXCL12 (C-X-C Motif Chemokine Ligand 12) • CD5 (CD5 Molecule) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • SYK (Spleen tyrosine kinase)
|
BTK C481S • PLCG2 mutation • BTK mutation
|
ibrutinib • Velexbru (tirabrutinib)
almost2years
Noncatalytic Bruton's tyrosine kinase activates PLCγ variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells. (PubMed, J Biol Chem)
At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca]. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.
Journal
|
BTK (Bruton Tyrosine Kinase) • PLCG2 (Phospholipase C Gamma 2) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase)
|
BTK C481S • PLCG2 mutation • BTK S707Y
|
ibrutinib
almost2years
Non-catalytic Bruton's tyrosine kinase activates PLCγ variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells. (PubMed, J Biol Chem)
Here, using genetically modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca]) we show that various CLL-specific PLCγ variants such as PLCγS707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ phospholipid substrate supply. At high levels of B cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically inactive BTK restored the ability of the BCR to mediate increases in [Ca] Since catalytically inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving non-catalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.
Journal
|
BTK (Bruton Tyrosine Kinase) • PLCG2 (Phospholipase C Gamma 2) • SYK (Spleen tyrosine kinase)
|
BTK C481S • PLCG2 mutation
|
ibrutinib