Abstract
Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9–3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.
Highlights
Waldenstrom macroglobulinemia (WM), a rare non-Hodgkin lymphoma variant, is characterized by unrestrained clonal proliferation of lymphoplasmacytic cells in the bone marrow and lymphoid tissue
As BTKC481S and CXCR4WHIM-like mutations have been reported to contribute towards ibrutinib resistance,[20,27] we sequenced the corresponding DNA regions and found neither BTKC481S nor CXCR4WHIM-like mutation in any of the WT or ibrutinib-resistant WM cells by either whole-exome or Sanger sequencing (Figures 1c–f and Supplementary Figure S1)
These findings suggested that ibrutinib resistance in WM cells can emerge without the presence of BTKC481S or CXCR4WHIM-like mutations, indicating other potential mechanisms for WM cell survival in the presence of sustained Brutons tyrosine kinase (BTK) inhibition
Summary
Waldenstrom macroglobulinemia (WM), a rare non-Hodgkin lymphoma variant, is characterized by unrestrained clonal proliferation of lymphoplasmacytic cells in the bone marrow and lymphoid tissue (lymph nodes, spleen). A first-in-class Brutons tyrosine kinase (BTK) inhibitor, is the first drug to gain Food and Drug Administration approval for treatment of WM and represents a milestone for patients suffering from this malignancy. In a phase II trial, relapsed or refractory WM patients who received ibrutinib demonstrated an overall response rate of 90.5%, with a major response rate of 70.5%. Estimated progression-free and overall survival (OS) at 24 months of treatment was 69.1% (95% confidence interval (CI): 53.2–80.5) and 95.2% (95% CI: 86.0–98.4), respectively.[3] no complete remissions were observed, indicating the WM cell’s ability to maintain their survival under ibrutinib-induced stress
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