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Table 7 Summary of observed mechanisms underlying drug resistance in DLBCL

From: Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review

Resistance mechanisms

Resistance type

Examples of molecules involved in

Examples of drugs affected

Study

Upregulation or constitutive activation of pro-survival pathways

Intrinsic genetic resistance

Treatment acquired resistance

BCL2 family/c-MYC (↑)

Proteasome inhibitors

[209, 625]

BCR signaling (↑), NF-κB (↑)

JAK/STAT3 signaling (↑)

(Bortezomib), CHOP, Rituximab

[107, 138, 164, 169, 171, 218, 366, 398, 407, 626]

PAK1 (MEK/ERK, PI3K/AKT, WNT/β-catenin signaling) (↑)

PI3K, mTORC1/2 inhibitors

 

Downregulation or inactivation of pro- apoptotic pathways

Intrinsic genetic resistance Treatment acquired resistance

TP53 (↓/Mutated)

Cisplatin, cytarabine, doxorubicin, etoposide, (−> CHOP, ICE, DHAP etc.)

[627–629]

Metabolic detoxification of drugs

Intrinsic genetic resistance Treatment acquired resistance

ALDH1A1, GPX1

Doxorubicin (−> CHOP)

[630]

Upregulation or constitutive activation of DNA damage signaling pathways

Intrinsic genetic resistance

Treatment acquired resistance

CHK1/2 (↑)

DTX3L, ARTD9 (↑)

Doxorubicin (−> CHOP)

[470, 547, 548, 631, 632]

Upregulation of multi-drug export machines

Intrinsic genetic resistance

Treatment acquired resistance

ABCB1, ABCG2 (↑)

Doxorubicin (−>CHOP), methotrexate, fludarabine, adriamycin, vinblastine

[220, 630, 633]

Upregulation or (constitutive) activation of alternative pro-survival pathways

Intrinsic genetic resistance

Treatment acquired resistance

MCL1, BFL1 (↑)

BCL2 inhibitors (ABT-737)

[363, 364]

HSP27, HSP70, HSP90 (↑)

MCL1, BCL-XL (↑)

HDAC3 (↑)

Proteasome inhibitors

(Bortezomib)

Rituximab

[166, 268, 371, 560, 561]

CARD11 mutant or MyD88 mutant mediated signaling -> NF-κB (↑)

BTK inhibitors (Ibrutinib)

[104, 259, 634]

Loss of key negative regulators of pro-survival signaling pathways

Intrinsic genetic resistance Treatment acquired resistance

4EBP1 (↓) - > mTORC1 pathway (↑)

mTORC1 inhibitors

[635]

Mutation(s) in target molecules or target pathways

Treatment acquired resistance

Ibrutinib binding site mutations in BTK.

Gain-of-function mutation in PLCγ2 -> BCR signaling (↑)

BTK inhibitors (Ibrutinib)

[465]

Downregulation of target molecules

 

CD20 (↓)

Rituximab

[223–227]

TME induced up regulation of pro-survival signaling pathways

Treatment acquired resistance

TME mediated resistance

BCR signaling (↑)

ABCG2 (↑)

BCL2, BCL-XL, BCL2A1 (↑)

CHOP

[217, 218]

[633]

  1. CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone, DHAP cisplatin, cytarabine, dexamethasone, etoposide, VIM ifosfamide, methotrexate, ESHAP etoposide, steroids, ara-C, and cisplatin, ICE ifosfamide, carboplatin, etoposide, GDP gemcitabine, cisplatin, and dexamethasone, BEAM carmustine, etoposide, cytarabine, melphala, MDR multi drug resistance, BCR B cell receptor, NF-κB nuclear factor-kappa B, JAK Janus kinase, STAT signal transducer and activator of transcription, PAK1 p21-activated kinase 1, CHK1/2 Chk1 protein kinase 1/2, DTX3L deltex (DTX)-3-like E3 ubiquitin ligase, ARTD9 ADP-ribosyltransferase-9 diphteria toxin like, BCL B-cell lymphoma protein, MCL1 myeloid cell leukemia 1, HSPs heat shock proteins, HDAC histone deacetylase, CARD11 caspase recruitment domain family, member 11, MyD88 myeloid differentiation primary response 88, 4EBP1 eukaryotic translation initiation factor 4E binding protein 1, mTORC1, mammalian target of rapamycin (mTOR) complex 1, ALDH1A1 aldehyde dehydrogenase 1A1, GPX1 glutathione peroxidase 1, ABCG2 ATP-binding cassette, sub-family G, member 2, ABCB1 ATP-binding cassette, sub-family B (MDR/TAP), member 1, PLCγ2 phospholipase C gamma 2, BTK Bruton’s tyrosine kinase, TME tumor microenvironment
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Molecular Cancer

ISSN: 1476-4598