#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Complex mechanisms of action of „BCR signalling“ inhibitors and development of resistance to this targeted therapy in chronic lymphocytic leukaemia


Authors: Ľ. Košťálová 1,2;  V. Šeda 1,2;  M. Mráz 1,2
Authors‘ workplace: CEITEC – Středoevropský technologický institut, Masarykova univerzita, Brno 1;  Interní hematologická a onkologická klinika FN Brno a LF MU, Masarykova univerzita, Brno 2
Published in: Transfuze Hematol. dnes,25, 2019, No. 4, p. 301-308.
Category: Review/Educational Papers

Overview

The emergence of the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib represented a revolution in the therapy of B cell malignancies. In some of these malignancies, they became the primary therapeutic strategy. However „BCR inhibitors“ function by a more complex mechanism than anticipated. The evolution of point mutations, chromosomal aberrations and changes in the physiology of malignant B cells leads to resistance in some patients treated with „BCR inhibitors“. The most commonly described aberration is the mutation in PLCγ bypassing BCR signalosome or the mutation in BTK preventing the covalent binding of ibrutinib. However, additional mutations leading to resistance are still being described. Furthermore, relative resistance to „BCR inhibitors“ can be caused by non-genetic adaptive mechanisms leading to activation of alternative pathways and „compensation“ of kinase inhibition. For instance, PI3K-Akt and NFκB activation or BCL2 upregulation lead to B cell survival even after BTK inhibition. This suggests some potentially effective therapeutic combinations of BTK/PI3K inhibitors together with other targeted inhibitors for clinical trials. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and migration of malignant B cells (chemokine and integrin pathway inhibition) or to block the pro-proliferative signals from the microenvironment such as IL4 (STAT inhibitors).

Keywords:

resistance – ibrutinib – idelalisib – CLL – BCR – inhibition – microenvironment


Sources

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369(1):32–42.

2. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370(11):997–1007.

3. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 2015;94(3):193–205.

4. D‘Avola A, Drennan S, Tracy I, et al. Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL. Blood 2016;128(6):816–826.

5. Mraz M, Chen L, Rassenti LZ, et al. miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood 2014;124(1):84–95.

6. Devan J, Janikova A, Mraz M. New concepts in follicular lymphoma biology: From BCL2 to epigenetic regulators and non-coding RNAs. Semin Oncol 2018;45(5-6):291–302.

7. Mraz M, Trbusek M, Dolezalova D, et al. Identifikace patogeneticky vyznamnych mutaci u chronicke lymfocytarni leukemie pomoci „sekvenovani nove generace“. Transfuze Hematologie dnes 2012;18(2):72–75.

8. Stamatopoulos B, Smith T, Crompot E, et al. The light chain IgLV3-21 defines a new poor prognostic subgroup in chronic lymphocytic leukemia: results of a multicenter study. Clin Cancer Res 2018;24(20):5048–5057.

9. Stamatopoulos K, Agathangelidis A, Rosenquist R, Ghia P. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia 2017;31(2):282–291.

10. Mráz M, Pavlová Š, Malčíková J, Malinová K, Mayer J, Pospíšilová, Š. Molekulární patogeneze chronické lymfocytární leukemie. Transfuze Hematol dnes 2010;16(1):16–20.

11. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 2005;105(5):2036–2041.

12. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004;351(9):893–901.

13. Lafarge ST, Li H, Pauls SD, et al. ZAP70 expression directly promotes chronic lymphocytic leukaemia cell adhesion to bone marrow stromal cells. Br J Haematol 2015;168(1):139–142.

14. Pavlasova G, Borsky M, Svobodova V, et al. Rituximab primarily targets an intra-clonal BCR signaling proficient CLL subpopulation characterized by high CD20 levels. Leukemia 2018;32(9):2028–2031.

15. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011;117(2):563–574.

16. Kneitz C, Goller M, Wilhelm M, et al. Inhibition of T cell/B cell interaction by B-CLL cells. Leukemia 1999;13(1):98–104.

17. Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim Biophys Acta 2016;1863(3):401–413.

18. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell‘Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 2000;96(8):2655–2663.

19. Aguilar-Hernandez MM, Blunt MD, Dobson R, et al. IL-4 enhances expression and function of surface IgM in CLL cells. Blood 2016;127(24):3015–3025.

20. Shanafelt TD, Geyer SM, Bone ND, et al. CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential. Br J Haematol 2008;140(5):537–546.

21. Mraz M, Zent CS, Church AK, et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol 2011;155(1):53–64.

22. Pavlasova G, Borsky M, Seda V, et al. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood 2016;128(12):1609–1613.

23. Burger M, Hartmann T, Krome M, et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 2005;106(5):1824–1830.

24. Bürkle A, Niedermeier M, Schmitt-Gräff A, Wierda WG, Keating MJ, Burger JA. Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood 2007;110(9):3316–3325.

25. Till KJ, Lin K, Zuzel M, Cawley JC. The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood 2002;99(8):2977–2984.

26. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 2015;1(1):80–87.

27. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton‘s tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014;370(24):2286–2294.

28. Walliser C, Hermkes E, Schade A, et al. The Phospholipase Cγ2 mutants R665W and L845F identified in ibrutinib-resistant chronic lymphocytic leukemia patients are hypersensitive to the Rho GTPase Rac2 protein. J Biol Chem 2016;291(42):22136–22148.

29. Liu TM, Woyach JA, Zhong Y, et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 2015;126(1):61–68.

30. Rubio-Moscardo F, Blesa D, Mestre C, et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood 2005;106(9):3214–3222.

31. Cosson A, Chapiro E, Bougacha N, et al. Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1. Leukemia 2017;31(7):1625–1629.

32. Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun 2016;7:11589.

33. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signal-ling in diffuse large B-cell lymphoma. Nature 2010;463(7277):88–92.

34. Wilson WH, Gerecitano JF, Goy A, et al. The Brutons tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Blood 2012;120 (21): 686 LP-686.

35. Phelan JD, Young RM, Webster DE, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature 2018;560(7718):387–391.

36. Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) sup-ports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood 2013;122(7):1222–1232.

37. Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom‘s macroglobulinemia. Leukemia 2015;29(1):169–176.

38. Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nat Med 2014;20(1):87–92.

39. Byrd JC, Smith S, Wagner-Johnston N, et al. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget 2018;9(16):13023–13035.

40. Lee SK, Xing J, Catlett IM, et al. Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants. Eur J Clin Pharmacol 2017;73(6):689–698.

41. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 2014;124(24):3583–3586.

42. Vakkalanka S, Nyayapathy S, Viswanadha S. Addition of RP6530, a dual PI3K delta/gamma inhibitor, overcomes ibrutinib resistance in DLBCL cells in vitro. Blood 2014;124(21):4497.

43. Pujala B, Agarwal AK, Middya S, et al. Discovery of pyrazolopyrimidine derivatives as novel dual inhibitors of BTK and PI3Kδ. ACS Med Chem Lett 2016;7(12):1161–1166.

44. Steele AJ, Prentice AG, Cwynarski K, et al. The JAK3-selective inhibitor PF-956980 reverses the resistance to cytotoxic agents induced by interleukin-4 treatment of chronic lymphocytic leukemia cells: potential for reversal of cytoprotection by the microenvironment. Blood 2010;116(22):4569–4577.

45. Guo A, Lu P, Coffey G, Conley P, Pandey A, Wang YL. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. Oncotarget 2017;8(8):12953–12967.

46. Spaner DE, McCaw L, Wang G, Tsui H, Shi Y. Persistent janus kinase-signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial. Cancer Med 2019;8(4):21540–21550.

47. Zuehlke A, Johnson JL. Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers 2010;93(3):211–217.

48. Jacobson C, Kopp N, Layer JV, et al. HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma. Blood 2016;128(21):2517–2526.

49. Zhong Y, El-Gamal D, Dubovsky JA, et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia 2014;28(5):1158–1163.

50. Hing ZA, Mantel R, Beckwith KA, et al. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood 2015;125(20):3128–3132.

Labels
Haematology Internal medicine Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#