Drug Resistance in Non-Hodgkin Lymphomas

Abstract

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20^th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

Keywords: chemotherapy; drug resistance; non-Hodgkin lymphomas; targeted agents.

Figure 1

Resistance to therapy. A. Low level of genomic heterogeneity—lymphoma population without preexisting drug-resistant cells. B. Intermediate level of genomic heterogeneity—lymphoma population with the preexisting drug-resistant clone resistant to induction therapy; C. High-level of genomic heterogeneity—lymphoma population with several clones resistant to diverse immunochemotherapy regimens; DTP—drug-tolerant persister cells.

Figure 2

Cell-intrinsic mechanisms of drug resistance. 1. Inhibition of active drug transport within the lymphoma cell; 2. Inhibition of pro-drug activation into active metabolite(s); 3. Increased drug degradation; 4. Increased drug efflux; 5. Interference with drug mode of action, e.g., increased DNA repair; 6. Disruption of DNA damage response pathways.

Figure 3

Cell-extrinsic mechanisms of drug resistance. 1. Hypoxia; 2. Acidosis; 3. Pro-survival growth factors and/or cytokines; 4. Cell-cell contact; 5. Alteration in the composition of extra-cellular matrix.

Figure 4

Hypoxic niche. Ox/Phos—oxidative phosphorylation, HIF1—hypoxia-inducible factor 1, PD1—programmed death 1, PD-L1—PD ligand 1, VEGF—vascular endothelial growth factor, O₂—oxygen, ROS—reactive oxygen species.

Figure 5

DNA damage response pathways. Double-strand DNA breaks: MRN—MRE11–RAD50–NBN (Nibrin) complex, ATM—ataxia-teleangiectasia mutated, BRCA1, BRCA2—breast-related cancer antigen 1, 2, XRCC2/3—X-ray repair cross complementing 2/3, DNA-PK—DNA protein-kinase, XRCC4—X-ray repair cross complementing 4, LIG4—DNA ligase 4, CHK2—check-point kinase 2, CDC25—cell division cycle 25; Single-strand DNA breaks: RPA—replication protein A, ATR—ataxia teleangiectasia and RAD3 related, CHK1—check-point kinase 1, CDC25C—cell division cycle 25C, PARP1—poly(ADP-ribose) polymerase 1, APE—exonuclease III APE, GLYC—DNA glycosylase, XRCC1—X-ray repair cross complementing 1, LIG—DNA ligase, POLB—DNA polymerase beta. Green—tumor suppressor genes recurrently mutated in lymphomas ATM, TP53, CHK1, CDKN2, red—oncogene BCL2 (B cell lymphoma 2) frequently overexpressed in lymphomas.

Figure 6

Downregulation of deoxycytidine-kinase confers resistance to a broad range of antinucleosides. HD-ara-C—high-dose cytarabine, ara-C—cytarabine, ara-CDP—Arabinofuranosylcytosine-diphosphate, ara-CMP—Arabinofuranosylcytosine-monophosphate, ara-CTP—Arabinofuranosylcytosine-trisphosphate, CDA—cytidine-deaminase, DCK—deoxycytidine-kinase, DCTD—deoxycytidine-monophosphate deaminase, dFd-C—gemcitabine, dFd-CDP—Difluorodeoxycytidine-diphosphate, dFd-CMP—Difluorodeoxycytidine-monophosphate, dFd-CTP—Difluorodeoxycytidine-triphosphate, F-ara-A—fludarabine, F-ara-AMP—9-β-D-arabinofuranosyl-2-fluoroadenine-monophosphate, F-ara-ADP—9-β-D-arabinofuranosyl-2-fluoroadenine-diphosphate, F-ara-ATP—9-β-D-arabinofuranosyl-2-fluoroadenine-triphophate, hNT—human nucleotide transporters, POL—DNA polymerase, 5-NT—5-nucleotidase.

Figure 7

B cell receptor and PI3K signaling. Abbreviations: AKT—protein kinase B/AKT, BCL10—B cell lymphoma 10, BCR—B-cell receptor signaling, BIRC3—Baculoviral IAP (inhibitor of apoptosis) Repeat Containing 3, BTK—Bruton tyrosine-kinase, CARD11—Caspase Recruitment Domain Family Member 11, CXCR4—C-X-C Motif Chemokine Receptor 4, DAG—diacylglycerol, ERK—extracellular signal-regulated kinase, FOXO—Forkhead Box O, GSK3β—glycogene synthase kinase 3 beta, LYN—Lck/Yes-Related Novel Protein Tyrosine Kinase, MALT1—Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1, MAP3K14—Mitogen-Activated Protein Kinase Kinase Kinase 14, MEK—mitogen-activated protein kinase kinase, MYD88—Myeloid Differentiation Primary Response Gene 88, mTOR—mammalian target of rapamycine, NFAT—nuclear factor of activated T-cells, NFκB—nuclear factor kappa B, PI3K—phosphatidylinositol 3-kinase, TLR—Toll-like receptor, PIP3—phosphoinositide 3,4,5-triphosphates, PIP2—phosphoinositide 4,5-diphosphosphate, PLCγ2—phospholipase C gamma 2, PTEN—phosphatase and tensin homolog, IP3—inositol 1,4,5-trisphosphate, RAF—RAF kinase, RAS—Raus sarcome oncogene, SHIP1—Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1, SYK—spleen tyrosine-kinase, S6K1—S6 kinase 1, TRAF2/3—Tumor Necrosis Factor Type 2 Receptor Associated Protein 2/3, 4E-BP—4E-binding protein. Asterisks highlight genes recurrently found in patients with lymphoma relapse after failure of ibrutinib.

Figure 8

Overexpression of MCL1 is associated with acquired resistance of MCL cells to venetoclax. A. Mode of action of venetoclax in venetoclax-sensitive lymphoma cells. B. Overexpression of MCL1 leads to resistance to venetoclax. BH3—BCL2 homology 3.