BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB

Rushworth, Stuart A.; Bowles, Kristian M.; Barrera, Lawrence N.; Murray, Megan Y.; Zaitseva, Lyubov; MacEwan, David J.

doi:10.1016/j.cellsig.2012.09.008

Cited by 99 publications

(101 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, pro-survival NF-kB signaling pathway members were also found to have a broader than anticipated profile in MM whole genome sequencing data. 6 These findings are consistent with our previous studies into the role of NF-kB signaling in haematological malignancies, [17][18][19] suggesting that a greater understanding of the NF-kB signaling network in bortezomib-resistant MM may be central to achieving therapeutic advances in this disease.…”

Section: Introductionsupporting

confidence: 88%

“…17 Furthermore, others have shown that bortezomib can reduce the expression of BTK mRNA and protein via an NF-kB p65-dependent mechanism. 22 We therefore examined whether BTK expression and activity in bortezomib-resistant MM cell lines reflects a mechanistic change in the BTK pro-survival signaling pathway in response to bortezomib treatment.…”

Section: 31mentioning

confidence: 99%

“…17,23 Specifically, we have shown that the irreversible BTK inhibitor ibrutinib can enhance the action of bortezomib via repression of the NF-kB survival pathway in primary tissue, e.g., bone marrow-derived MM cells from treatment-na€ ıve patients. 17 Despite these findings, however, early phase II clinical trial data for ibrutinib monotherapy in MM have so far proved disappointing, 28 while the study of ibrutinib efficacy in patients with relapsed of refractory MM is currently recruiting (ClinicalTrials.gov Identifier:NCT01478581).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

Self Cite

View full text Add to dashboard Cite

Abbreviations: MM -multiple myeloma; PI -proteasome inhibitor; NF-kB -nuclear factor-kappa B; BMSC -bone marrow stromal cells; BTK -Bruton's tyrosine kinase.Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n D 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n D 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 mM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-kB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-kB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-kB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 § 6 .9 %, ANOVA P 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.

show abstract

Section: Introductionsupporting

confidence: 88%

Section: 31mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, the inhibition of BTK induces cytotoxicity in human MM cells (Rushworth et al , 2013), providing a scientific rationale for investigating ibrutinib as a therapeutic option for MM as a new combination partner with a novel mechanism of action. Preclinical studies have also demonstrated that ibrutinib could act synergistically with common backbone agents.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have also demonstrated that ibrutinib could act synergistically with common backbone agents. Evidence of synergy between ibrutinib and the IMiD lenalidomide and the PI bortezomib has been observed in both MM patient cells and in MM cell lines, as evidenced by an increased cytotoxicity of malignant plasma cells (Rushworth et al , 2013). Additional preclinical data suggest that both BTK inhibitors and IMiDs target the clonogenic side populations of CD138 neg cells, which are capable of clonogenic growth, self‐renewal and differentiation into myeloma plasma cells (Yang et al , 2006; Jakubikova et al , 2011; Beauvais et al , 2016).…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

et al. 2018

View full text Add to dashboard Cite

SummaryNovel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.

show abstract

The genetics of mature B‐cell malignancies

Strefford¹,

Fitzgibbon²,

Rose-Zerilli³

et al. 2016

The Genetic Basis of Haematological Cancers

View full text Add to dashboard Cite

BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB

Cited by 99 publications

References 27 publications

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

The genetics of mature B‐cell malignancies

Contact Info

Product

Resources

About