Skip to main content
SpringerLink
Log in
Book cover

Resistance of Targeted Therapies Excluding Antibodies for Lymphomas pp 23–43Cite as

BCL2 Inhibitors: Insights into Resistance

  • Chapter
  • First Online:

  • 378 Accesses

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 17))

Abstract

Over the last decade, improved understanding of the mechanisms and structures of proteins integral to apoptosis have enabled therapeutic targeting of BCL2 to become more specific, less toxic and ultimately more clinically effective. The first BCL2-selective inhibitor, venetoclax, is now approved for use in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) in multiple countries. Early phase clinical trials demonstrated an 80% overall response rates in patients with relapsed/refractory CLL, independent of traditional risk factors, without undue toxicity. Venetoclax is also highly active in other lymphoid malignancies that express high levels of its target, BCL2, such as mantle cell lymphoma. However, there is a cumulative incidence of disease progression while on therapy. Ongoing follow-up of the early phase trials is only now enabling elucidation of the incidence and risk factors for disease progression and treatment failure. Preventing development of resistance to BCL2 inhibition requires further research aimed at delineating the genetic and epigenetic drivers of disease progression. This will facilitate targeting of resistance mechanisms through the use of rational drug combinations, help to prospectively identify patients most likely to benefit and abet early identification of emerging resistance. These therapies are improving outcomes for patients with previously poor prognosis disease.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

AML:

Acute myeloid leukemia

BCL2:

B cell lymphoma 2

BCR:

B cell receptor

BH:

BCL2 homology

BTK:

Burtons tyrosine kinase

CI:

Confidence interval

CLL:

Chronic lymphocytic leukemia

CR:

Complete remission

CRi:

Complete remission, incomplete count recovery

Del11q:

Deletion 11q

Del17p:

Deletion 17p

DLBCL:

Diffuse large B cell lymphoma

DLT:

Dose limiting toxicity

DOR:

Duration of response

EC50 :

Half maximal effective concentration

EFS:

Event free survival

FFP:

Freedom from progression

FL:

Follicular lymphoma

G:

Grade

HL:

Hodgkin lymphoma

IDH:

Isocitrate dehydrogenase

IGVH:

Immunoglobulin variable region heavy chain

IHC:

Immunohistochemistry

MCL:

Mantle cell lymphoma

MLL:

Mixed lineage leukemia

MM:

Multiple myeloma

MRD:

Minimal residual disease

MTD:

Maximum tolerated dose

MZL:

Marginal zone lymphoma

NA:

Not applicable

NHL:

Non-Hodgkin lymphoma

nM:

Nano-molar

ORR:

Overall response rate

OS:

Overall survival

PD:

Progressive disease

PFS:

Progression free survival

PI3κ:

Phosphoinositide 3 kinase

PR:

Partial response

RP2D:

Recommended phase 2 dose

RT:

Richter’s transformation

SLL:

Small lymphocytic lymphoma

TLS:

Tumor lysis syndrome

TTP:

Time to progression

WM:

Waldenstrom’s macroglobulinemia

References

  1. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.

    Article  CAS  PubMed  Google Scholar 

  2. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005;105:49–53.

    Article  CAS  PubMed  Google Scholar 

  3. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6.

    Article  PubMed  Google Scholar 

  4. Mayr C, Speicher MR, Kofler DM, et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006;107:742–51.

    Article  CAS  PubMed  Google Scholar 

  5. Tam CS, O'Brien S, Lerner S, et al. The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma. 2007;48:1931–9.

    Article  CAS  PubMed  Google Scholar 

  6. Zenz T, Gribben JG, Hallek M, et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012;119:4101–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1756–65.

    Article  CAS  PubMed  Google Scholar 

  8. Keating MJ, O'Brien S, Kantarjian H, et al. Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood. 1993;81:2878–84.

    CAS  PubMed  Google Scholar 

  9. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.

    CAS  PubMed  Google Scholar 

  11. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med. 2009;361:1570–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  17. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  18. Strasser A, Harris AW, Jacks T, Cory S. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell. 1994;79:329–39.

    Article  CAS  PubMed  Google Scholar 

  19. Schmitt CA, Rosenthal CT, Lowe SW. Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med. 2000;6:1029–35.

    Article  CAS  PubMed  Google Scholar 

  20. Huang DC, O'Reilly LA, Strasser A, Cory S. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J. 1997;16:4628–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Miyashita T, Reed JC. Bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 1992;52:5407–11.

    CAS  PubMed  Google Scholar 

  22. Miyashita T, Reed JC. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood. 1993;81:151–7.

    CAS  PubMed  Google Scholar 

  23. Kamesaki S, Kamesaki H, Jorgensen TJ, et al. Bcl-2 protein inhibits etoposide-induced apoptosis through its effects on events subsequent to topoisomerase II-induced DNA strand breaks and their repair. Cancer Res. 1993;53:4251–6.

    CAS  PubMed  Google Scholar 

  24. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51:219–27.

    Article  CAS  PubMed  Google Scholar 

  25. Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005;17:393–403.

    Article  CAS  PubMed  Google Scholar 

  26. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993;75:229–40.

    Article  CAS  PubMed  Google Scholar 

  27. Merino D, Khaw SL, Glaser SP, et al. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood. 2012;119:5807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128:1173–86.

    Article  CAS  PubMed  Google Scholar 

  29. Peperzak V, Vikstrom I, Walker J, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013;14:290–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001;292:727–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zong WX, Lindsten T, Ross AJ, et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 2001;15:1481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985;228:1440–3.

    Article  CAS  PubMed  Google Scholar 

  33. Tsujimoto Y, Croce CM. Recent progress on the human bcl-2 gene involved in follicular lymphoma: characterization of the protein products. Curr Top Microbiol Immunol. 1988;141:337–40.

    CAS  PubMed  Google Scholar 

  34. Robertson LE, Plunkett W, McConnell K, et al. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996;10:456–9.

    CAS  PubMed  Google Scholar 

  35. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci. 2002;99:15524–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pettersson M, Jernberg-Wiklund H, Larsson LG, et al. Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells. Blood. 1992;79:495–502.

    CAS  PubMed  Google Scholar 

  37. Agarwal B, Naresh KN. Bcl-2 family of proteins in indolent B-cell non-Hodgkin's lymphoma: study of 116 cases. Am J Hematol. 2002;70:278–82.

    Article  CAS  PubMed  Google Scholar 

  38. Vijay A, Gertz MA. Waldenstrom macroglobulinemia. Blood. 2007;109:5096–103.

    Article  CAS  PubMed  Google Scholar 

  39. Aisenberg AC, Wilkes BM, Jacobson JO. The bcl-2 gene is rearranged in many diffuse B-cell lymphomas. Blood. 1988;71:969–72.

    CAS  PubMed  Google Scholar 

  40. Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989–1000.

    Article  CAS  PubMed  Google Scholar 

  41. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996;274:1531–4.

    Article  CAS  PubMed  Google Scholar 

  42. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–81.

    Article  CAS  PubMed  Google Scholar 

  43. Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–8.

    Article  CAS  PubMed  Google Scholar 

  44. Wilson WH, O'Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11:1149–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30:488–96.

    Article  CAS  PubMed  Google Scholar 

  46. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.

    Article  CAS  PubMed  Google Scholar 

  47. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22.

    Article  CAS  PubMed  Google Scholar 

  48. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–99.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mason KD, Vandenberg CJ, Scott CL, et al. In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas. Proc Natl Acad Sci USA. 2008;105:17961–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kang MH, Kang YH, Szymanska B, et al. Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood. 2007;110:2057–66.

    Article  CAS  PubMed  Google Scholar 

  51. Kline MP, Rajkumar SV, Timm MM, et al. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia. 2007;21:1549–60.

    Article  CAS  PubMed  Google Scholar 

  52. Mason KD, Khaw SL, Rayeroux KC, et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia. 2009;23:2034–41.

    Article  CAS  PubMed  Google Scholar 

  53. Ackler S, Mitten MJ, Foster K, et al. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother Pharmacol. 2010;66:869–80.

    Article  CAS  PubMed  Google Scholar 

  54. Roberts AW, Advani RH, Kahl BS, et al. Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies. Br J Haematol. 2015;170:669–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kipps TJ, Eradat H, Grosicki S, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:2826–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kipps TJ, Swinnen LJ, Wierda WG, et al. Navitoclax (ABT-263) plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): a phase 1 study in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL). Blood. 2011;118:3904.

    Google Scholar 

  57. Zhang H, Nimmer PM, Tahir SK, et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007;14:943–51.

    Article  CAS  PubMed  Google Scholar 

  58. Khaw SL, Merino D, Anderson MA, et al. Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. Leukemia. 2014;28:1207–15.

    Article  CAS  PubMed  Google Scholar 

  59. Gong JN, Khong T, Segal D, et al. Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016;14:1834–44.

    Article  Google Scholar 

  60. Vogler M, Dinsdale D, Dyer MJ, Cohen GM. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol. 2013;163:139–42.

    Article  CAS  PubMed  Google Scholar 

  61. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism. Blood. 2016;127(25):3215–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chiron D, Dousset C, Brosseau C, et al. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget. 2015;6:8750–9.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Cao Y, Hunter ZR, Liu X, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;168:701–7.

    Article  CAS  PubMed  Google Scholar 

  64. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210–2.

    Article  CAS  PubMed  Google Scholar 

  65. Khaw SL, Suryani S, Evans K, et al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood. 2016;128:1382–95.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Benito JM, Godfrey L, Kojima K, et al. MLL-rearranged acute lymphoblastic Leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep. 2015;13:2715–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4:362–75.

    Article  CAS  PubMed  Google Scholar 

  68. Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Davids M, Roberts A, Seymour J, et al. A phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Seymour J, Ma S, Phase BD. 1b study of venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia. Lancet Oncol. 2017;18(2):230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.

    Article  CAS  PubMed  Google Scholar 

  72. Edwards SK, Han Y, Liu Y, et al. Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells. Leuk Res. 2016;41:85–95.

    Article  CAS  PubMed  Google Scholar 

  73. Qin JZ, Ziffra J, Stennett L, et al. Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res. 2005;65:6282–93.

    Article  CAS  PubMed  Google Scholar 

  74. Moreau P, Chanan-Khan A, Roberts AW, et al. Safety and efficacy of Venetoclax (ABT-199/GDC-0199) in combination with Bortezomib and dexamethasone in relapsed/refractory multiple myeloma: phase 1b results. Blood. 2015;126:3038–8.

    Google Scholar 

  75. DiNardo C, Pollyea D, Pratz K, et al. A phase 1b study of Venetoclax (ABT-199/GDC-0199) in combination with Decitabine or Azacitidine in treatment-naive patients with acute Myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Blood. 2015;126:327.

    Article  Google Scholar 

  76. Lew TE, Anderson MA, Tam CS, et al. Clinicopathological features and outcomes of progression for Chronic Lymphocytic Leukaemia (CLL) treated with the BCL2 inhibitor venetoclax. Blood. 2016;128:3223.

    Google Scholar 

  77. Davids MS, Roberts AW, Seymour JF, et al. Safety, efficacy and immune effects of venetoclax 400 mg daily in patients with relapsed chronic lymphocytic leukemia (CLL). J Clin Oncol (Meeting Abstracts). 2016;34:7527.

    Google Scholar 

  78. Fresquet V, Rieger M, Carolis C, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123:4111–9.

    Article  CAS  PubMed  Google Scholar 

  79. Bodo J, Zhao X, Durkin L, et al. Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells. Oncotarget. 2016;7:70000–10.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Punnoose EA, Leverson JD, Peale F, et al. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist Venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1132–44.

    Article  CAS  PubMed  Google Scholar 

  81. Choudhary GS, Tat TT, Misra S, et al. Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics. Oncotarget. 2015;6:16912–25.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Bojarczuk K, Sasi BK, Gobessi S, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–201.

    Article  CAS  PubMed  Google Scholar 

  83. Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100:e302–6.

    PubMed  PubMed Central  Google Scholar 

  84. Chiron D, Bellanger C, Papin A, et al. Lymphoid-like environment, which promotes proliferation and induces resistance to BH3-Mimetics, is counteracted by Obinutuzumab in MCL: biological rationale for the oasis clinical trial. Blood. 2016;128:1096.

    Article  Google Scholar 

  85. Kumar S, Vij R, Kaufman J, et al. Phase 1 study of Venetoclax monotherapy for relapsed/refractory multiple myeloma. In Haematologica. Ferrata Storti Foundation Via Giuseppe Belli 4, 27100 Pavia, Italy 2016:328–328.

    Google Scholar 

  86. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of Venetoclax monotherapy in patients with acute Myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Parkville, VIC, Australia

    Mary Ann Anderson, Andrew W. Roberts & John F. Seymour

  2. Division of Cancer and Haematology, Walter and Eliza Hall Institute, Parkville, VIC, Australia

    Mary Ann Anderson & Andrew W. Roberts

  3. The University of Melbourne, Melbourne, VIC, Australia

    Andrew W. Roberts & John F. Seymour

Authors
  1. Mary Ann Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew W. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John F. Seymour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John F. Seymour .

Editor information

Editors and Affiliations

  1. Department of Onco-Hematology, Unit of Lymphoid Malignancies, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Andrés J. M. Ferreri

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Anderson, M.A., Roberts, A.W., Seymour, J.F. (2018). BCL2 Inhibitors: Insights into Resistance. In: Ferreri, A. (eds) Resistance of Targeted Therapies Excluding Antibodies for Lymphomas. Resistance to Targeted Anti-Cancer Therapeutics, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-319-75184-9_2

Download citation

Publish with us

Policies and ethics

Search

Navigation