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Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib

Reiff, Sean
http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Chronic lymphocytic leukemia (CLL) is a cancer of monoclonal B cells caused by dysregulated proliferation within the bone marrow which disrupts normal hematopoiesis leading to anemia, immune deficiencies, and increased rates of morbidity and mortality. With approximately 150,000 affected individuals and an annual incidence exceeding 20,000 in the United States, CLL is the most prevalent leukemia in the western hemisphere. Recent appreciation for the extent to which B cell receptor (BCR) signaling contributes to the pathogenesis of CLL has spurred the development of small molecule inhibitors which block signaling initiated at the BCR. One such molecule designed to abrogate BCR signaling is ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Patients treated with ibrutinib benefit from durable remission and prolonged progression free survival. However, despite ibrutinib’s multiple Breakthrough Therapy Designation, it is not a panacea and resistance to therapy occurs in many patients. Resistance to ibrutinib is most commonly mediated by mutation of BTK’s Cys481 amino acid to serine (C481S), which prevents ibrutinib’s covalent binding, reducing its potency. The kinase inhibitors GDC-0853 and ARQ 531 reversibly and potently inhibit BTK at low nanomolar concentrations. Like ibrutinib, these compounds are mildly cytotoxic, reduce chemotaxis, and abrogate NF-kB mediated gene transcription. Because GDC-0853 and ARQ 531 are reversible inhibitors which do not rely upon the Cys481 amino acid of BTK for activity, we hypothesized that these compounds would maintain efficacy in mutated C481S BTK. As expected, both GDC-0853 and ARQ 531 inhibit C481S BTK in biochemical assays, as well as cell lines and patient cells expressing C481S BTK. While GDC-0853 possesses exquisite specificity for BTK, ARQ 531 is a relatively promiscuous kinase inhibitor which targets multiple SRC and TEC family kinases. Interestingly, their distinct inhibitory profiles bestow unique properties of potential clinical benefit. For example, GDC-0853 lacks the ITK inhibition possessed by ibrutinib. Because ITK is necessary for antibody dependent NK cell mediated cytotoxicity, immunotherapies are much more effectively combined with GDC-0853 than with ibrutinib. Conversely, our results with ARQ 531 suggest that non-specific kinase inhibition may also provide clinical benefit. In vivo, ARQ 531 improved survival over ibrutinib the Eµ-TCL1 murine model of CLL and improved survival in the Eµ-MYC/TCL1 murine model of Richter’s syndrome (in which ibrutinib was ineffective). Additionally, ARQ 531 inhibits downstream signaling in models with ibrutinib resistance due to PLC¿2 mutations. As the prevalence and duration of ibrutinib therapy continue to increase, so too will the incidence of ibrutinib resistance in patients. The observation that the majority of patients who develop resistance to ibrutinib do so by mutating components of the BCR pathway rather than by upregulating an accessory survival pathway indicates that BCR signaling is critical to CLL progression. Therefore, there is strong rationale to utilize reversible BTK inhibitors like GDC-0853 and ARQ 531 in order to maintain inhibitory pressure on BTK in the setting of ibrutinib resistance. Based upon the findings contained herein I propose that reversible BTK inhibition may be a viable therapeutic option for patients with acquired ibrutinib resistance.
John Byrd (Advisor)
Jennifer Woyach (Advisor)
Robert Baiocchi (Committee Member)
William Carson, III (Committee Member)
143 p.
Biomedical Research
chronic lymphocytic leukemia; BTK; ARQ 531; GDC-0853; ibrutinib resistance

Recommended Citations

Citations

  • Reiff, S. (2018). Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698

    APA Style (7th edition)

  • Reiff, Sean. Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698.

    MLA Style (8th edition)

  • Reiff, Sean. "Utilizing Reversible Bruton’s Tyrosine Kinase Inhibitors to Circumvent Acquired Resistance to Ibrutinib." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523372591057698

    Chicago Manual of Style (17th edition)

osu1523372591057698
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