ReviewCancer

Interrogating B cell signaling pathways: A quest for novel therapies for mantle cell lymphoma

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Sci. Signal.  05 Feb 2019:
Vol. 12, Issue 567, eaat4105
DOI: 10.1126/scisignal.aat4105

Figures

  • Fig. 1 Targeting the BCR-BTK signaling network in MCL.

    Small-molecule inhibitors of kinases involved in BCR signaling, such as those targeting SYK, are used to treat various hematopoietic malignancies. Targeting intracellular BCR signaling, such as the PI3K-AKT pathway (depicted further in Fig. 2), or by blocking the activity of BTK with ibrutinib and others has shown promising results in patients with MCL. However, the emergence of ibrutinib-resistant cells has become clinically problematic. Current research focuses on targeting molecules farther downstream to inhibit cell growth. Pathway depictions have been simplified. PIP2, phosphatidylinositol-4,5-bisphosphate; BCAP, B cell adaptor for PI3K; BLNK, B cell linker protein; PLCγ2, phospholipase C–γ2; β38-MAPK, β p38 mitogen-activated protein kinase; Ag, antigen; Ig-α, immunoglobulin-associated alpha; Ig-β, immunoglobulin-associated beta.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 2 The AKT network as a central therapeutic target in MCL.

    The AKT pathway is a major signaling network node that supports cell function, growth, and proliferation. Antigen binding to the BCR induces receptor clustering and transduction. Subsequent activation of PI3K through BCR-associated kinases (SYK or LYN) and the adaptor protein BCAP stimulates PI3K-mediated phosphorylation of the lipid PIP2 to form PIP3, which then recruits AKT and other proteins to the plasma membrane, thereby facilitating activation. Cell proliferation is blocked by inhibition of PI3K or the intracellular BCR mediators, SYK, or LYN (Fig. 1). By recruiting pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1) and AKT to the plasma membrane, PIP3 also activates PKC and mTORC1 and mTORC2, which are other potential targets for therapy. Pathway depictions have been simplified. PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; BAD, Bcl-2–associated death promoter; PIP5K, phosphatidylinositol-4-phosphate 5-kinase.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 3 Targeting NF-κB pathways in MCL.

    The NF-κB transcription factor family (RelA, RelB, c-Rel, p50, and p52) controls cell differentiation, survival, and proliferation. The BCR activates both the classical and alternative NF-κB pathways. Whereas the classical pathway is mediated by IKKβ-related RelA activation, the alternative pathway is mediated by IKKα/NIK complex-related RelB activation. The CBM signaling complex, comprising CARD11, BCL10, and MALT, plays a major upstream role in both pathways, as do proteasomal complexes downstream that enable the formation of transcriptionally active p50/RelA and p52/RelB complexes. Thus, NIK and the proteasome might be targeted for treating MCL. Pathway depictions have been simplified. TRAF, tumor necrosis factor receptor-associated factors; cIAP1/2, cellular inhibitors of apoptosis 1 and 2; BIRC, baculoviral IAP repeat containing gene; P, phosphorylation.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING

Tables

  • Table 1 B cell pathways frequently disrupted and therapeutic agents that inhibit key pathway molecules.

    Major B cell signaling pathways and its common mode of disruptions are shown. Within each pathway, key molecules or processes can be inhibited by various therapeutic agents, either FDA-approved or under development.

    Up-regulated
    pathways
    Mode of
    disruption
    Possible
    therapeutic
    agents
    Current
    settings
    BCR pathwaySomatic
    mutation
    BTK inhibitors:
    ibrutinib and
    acalabrutinib
    Ibrutinib:
    FDA-approved
    Acalabrutinib:
    FDA-approved
    (NCT02029443)
    NF-κВ pathwaySomatic
    mutation
    Angiogenesis
    inhibitor:
    lenalidomide
    Proteasome
    inhibitor:
    velcade
    (bortezomib)
    Lenalidomide:
    under FDA
    review
    Bortezomib:
    FDA-approved
    Cell cycle controlSomatic
    mutation;
    epigenetic
    suppression
    CDK4/CDK6
    inhibitor:
    abemaciclib
    Phase 3
    (FDA-approved
    for breast
    cancer)
    Apoptosis/p53
    pathway
    Somatic
    mutation
    Bcl-2 inhibitor:
    venetoclax
    AKT/ERK
    inhibitor:
    ONC201
    MDM2
    inhibitors
    Venetoclax:
    phase 2
    DNA damage repair
    pathway
    Somatic
    mutation:
    epigenetic
    suppression
    Poly
    ADP-ribose
    polymerase
    inhibitor:
    olaparib
    Phase 1
    PI3K pathwaySomatic
    mutation
    PI3K inhibitors:
    idelalisib,
    KA-2237, and
    TGR-1202
    Idelalisib: phase 1
    Oxidative
    phosphorylation
    (OXPHOS)
    pathway
    Metabolic
    disruption
    Mitochondrial
    complex I
    inhibitor:
    IACS-010759
    Phase 1
  • Table 2 Chemotherapy-free targeted regimens versus standard chemotherapy in MCL.

    Outcomes of chemotherapy-free regimens are shown for both newly diagnosed and relapsed patients with MCL, noting percent of patients with overall response, complete response, and toxicity. Standard chemotherapy is shown at the bottom of the table to primarily compare the toxicity effects on patients. Sources of data are cited in parentheticals, left column.

    Newly diagnosed patientsOverall responseComplete responseToxicity (grade ≥ 3)Secondary malignancy
    Therapy
    Lenalidomide + rituximab (41)92% (n = 36)64% (n = 36)Neutropenia, 50%; rash, 29%;
    thrombocytopenia, 13%;
    tumor flare, 11%; anemia,
    11%
    None
    Rituximab + ibrutinib (40)100% (n = 50)72% (n = 50)Fatigue, 6%None
    Ibrutinib + lenalidomide +
    Rituximab (65)
    83% (n = 29)41% (n = 29)Neutropenia, 38%; infections,
    22%; rash, 14%
    None
    Relapsed-refractory patients
    Ibrutinib + rituximab (38)88% (n = 50)44% (n = 50)Atrial fibrillation, 12%None
    Ibrutinib + venetoclax (42)71% (n = 17)67% (n = 16)Only low grade ≤ 3 diarrhea
    and fatigue
    None
    Acalabrutinib81% (n = 100)40% (n = 49)Neutropenia, 10%; anemia,
    9%
    None
    Chemotherapy
    Rituximab-hyper-
    cyclophosphamide
    vincristine adriamycin
    dexamathasone (R-Hyper-
    CVAD) (10, 72)
    96% (n = 97)54% (n = 97)Febrile neutropenia, 73%;
    hematotoxicity, >50%
    6.2%
    Rituximab-cyclophosphamide
    hydroxydaunomycin
    oncovin prednisone
    (R-CHOP)/maxi-CHOP (9)
    97% (n = 160)87% (n = 160)Febrile neutropenia, 75%;
    hematotoxicity, >50%
    9.4%
    Rituximab-bendamustine
    (R-Benda) (73)
    100% (n = 20)95% (n = 20)Thrombocytopenia, 87%;
    neutropenia, 29%
    6 to 11%

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