Drug Information

Drug (ID: DG00130) and It's Reported Resistant Information

• Name: Ibrutinib
• Synonyms: PCI-32765; Ibrutinib (BTK inhibitor)
• Indication:
  In total 6 Indication(s)
  Mature B-cell lymphoma [ICD-11: 2A85]; Approved; [1]
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; Phase 3; [1]
  Follicular lymphoma [ICD-11: 2A80]; Phase 3; [1]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 3; [1]
  Pancreatic cancer [ICD-11: 2C10]; Phase 3; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [2]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [4]
  Diffuse large B-cell lymphoma [ICD-11: 2A81]; [4]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [5]
• Target: Tyrosine-protein kinase BTK (ATK); BTK_HUMAN; [1]
• Formula: C25H24N6O2
• IsoSMILES: C=CC(=O)N1CCC[C@H](C1)N2C3=NC=NC(=C3C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)N
• InChI: 1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m1/s1
• InChIKey: XYFPWWZEPKGCCK-GOSISDBHSA-N
• PubChem CID: 24821094
• ChEBI ID: CHEBI:76612
• TTD Drug ID: D09KTS
• VARIDT ID: DR01270
• INTEDE ID: DR0843
• DrugBank ID: DB09053

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Diffuse large B-cell lymphoma [ICD-11: 2A81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [4]

• Molecule Alteration: Missense mutation; p.L265P
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Furthermore, within ABC DLBCL, responses were significantly different depending on the specific genetic lesions. Ibrutinib-resistant tumours carry mutant MYD88 and WT CD79A/B whereas all other genotypic combinations (CD79A/BWT + MYD88WT, CD79A/Bmutant + MYD88WT and CD79A/Bmutant + MYD88mutant) were responsive to ibrutinib therapy. It is foreseeable why ibrutinib therapy is less effective in MYD88-mutated ABC-DLBCL patients because MYD88 activates NFkappa-B through a parallel pathway independent of BTK. However, it is unclear why MYD88 mutations alone are associated with ibrutinib resistance whereas the MYD88 mutations in conjunction with CD79A/B mutations appears to render ABC DLBCL ibrutinib-sensitive.

Chronic lymphocytic leukemia [ICD-11: 2A82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase BTK (BTK) [2]

• Molecule Alteration: Missense mutation; p.C481R
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [2]

• Molecule Alteration: Missense mutation; p.C481S
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [4]

• Molecule Alteration: Missense mutation; p.C481S
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [2]

• Molecule Alteration: Missense mutation; p.S707Y
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [2]

• Molecule Alteration: Missense mutation; p.P664W
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [2]

• Molecule Alteration: Missense mutation; p.P664S
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [2]

• Molecule Alteration: Missense mutation; p.L845F
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [4]

• Molecule Alteration: Mutation; p.R665W+p.L845F+p.S707Y
• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: In contrast to the BTKC481S mutation, which causes eventual loss of BTK inhibition by ibrutinib, PLCG2 mutations are all potentially gain-of-function mutations. Situated downstream from BTK, PLCG2 mutations allow for continued signalling regardless of BTK activity. After stimulation with anti-IgM antibody, cells with either the PLCG2R665W or PLCG2L845F mutations were found to have sustained BCR signalling that was not inhibited by ibrutinib, as measured by calcium-flux assays and phosphorylation of ERK and AKT.

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase BTK (BTK) [6]

• Molecule Alteration: Missense mutation; p.C481S
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [6]

• Molecule Alteration: Missense mutation; p.C481S
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Key Molecule: Tyrosine-protein kinase BTK (BTK) [4]

• Molecule Alteration: Missense mutation; p.C481S
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PIK3/AKT signaling pathway; Activation; hsa04211
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ROR1 antisense RNA 1 (ROR1-AS1) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Granta cells; Peripheral blood; Homo sapiens (Human); N.A.
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: Overexpression of ROR1-AS1 LncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Molecule Alteration: Missense mutation; p.Y361C
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Molecule Alteration: Missense mutation; p.G123S
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Molecule Alteration: Missense mutation; p.D357E
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Molecule Alteration: Missense mutation; p.D230N
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [7]

• Molecule Alteration: Mutation; .
• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to ibrutinib in the waldenstrom macroglobulinemia.

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [4]

• Molecule Alteration: Mutation; p.S338X
• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Mechanism Description: CXCR4 is a transmembrance chemokine receptor that is internalized upon binding to its ligand CXCL12 and subsequently signals through G-proteins to activate the AKT and ERK pathways. The CXCR4 pathway plays an important role in lymphocyte migration and homing. CXCR4WHIM-like are prevalent somatic mutations, present in 30% of patients with WM. It was recently demonstrated that CXCR4S338X, the most common WHIM-like mutation, reduces CXCR4 receptor internalization and allows for sustained enzymatic activity of AKT and ERK and subsequent increased cell survival. When cells are exposed to ibrutinb, CXCR4S338X-carrying WM cells, compared to CXCR4WT cells, exhibit reduced apoptosis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [4]

• Molecule Alteration: Mutation; p.L265P
• Sensitive Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The mutant, as opposed to MYD88WT, preferentially binds to p-BTK and subsequently activates NFKB. Ibrutinib treatment reduces such binding, therefore blocking downstream NFKB activation. Thus, the oncogenic activity of MYD88L265P is mediated through BTK in WM and renders cells sensitive to ibrutinib's inhibition. The fact that MYD88 mutations function differently in different cells highlight the notion that impact of a particular genetic mutation has to be determined and understood within the particular cellular context.

Prostate cancer [ICD-11: 2C82]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-214 [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-214 targets PTk6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein-tyrosine kinase 6 (PTK6) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-214 targets PTk6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.

References

• Ref 1: MicroRNA-214 targets PTK6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells. Sci Rep. 2019 Jul 5;9(1):9776. doi: 10.1038/s41598-019-46170-3.
• Ref 2: Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
• Ref 3: Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. Oncotarget. 2016 Jun 21;7(25):38180-38190. doi: 10.18632/oncotarget.9500.
• Ref 4: Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427
• Ref 5: Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex. Oncotarget. 2017 May 17;8(46):80223-80234. doi: 10.18632/oncotarget.17956. eCollection 2017 Oct 6.
• Ref 6: Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects .Br J Haematol. 2018 May;181(3):306-319. doi: 10.1111/bjh.15108. Epub 2018 Jan 23. 10.1111/bjh.15108
• Ref 7: Genomics, Signaling, and Treatment of Waldenstr m Macroglobulinemia .J Clin Oncol. 2017 Mar 20;35(9):994-1001. doi: 10.1200/JCO.2016.71.0814. Epub 2017 Feb 13. 10.1200/JCO.2016.71.0814