Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas

Abstract

Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of and, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ∼30%, while ∼70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ∼25%. However, TGI for ibrutinib + rituximab was ∼50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. .

Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase

“…Equal number (n = 3) of LOF and GOF p53 samples define the Aur-A WT group, whereas equal number of Aur-A epiΔ ; LOF p53 and Aur-A epiΔ ; GOF p53 samples define the Aur-A epiΔ group multinucleated states; this may be an impediment to using anti-mitotic agents in skin cancer treatment. However, the use of anti-mitotic and mTOR/PI3K inhibitors may be an effective combination as recently shown for Large B-cell Lymphomas [67]. This combination may also be relevant for organ transplant patients who are at high risk of developing metastatic or recurring SCCs and whose immune systems are suppressed with the use of mTOR inhibitors [68].…”

Novel Aurora Kinase Inhibitor-Based Combination Therapies for PTCL

“…AK inhibition leads to catastrophic errors of mitosis, such as defective cytokinesis, misaligned centrosomes, and mitotic spindle malformation, culminating in apoptosis [60,61]. However, drug-resistant non-diploid cells can enter the cell cycle by reductive divisions during intermittent therapy [62]. Several AK inhibitors have been studied preclinically and clinically in trials for patients with r/r PTCL.…”

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

“…Due to sponsor decision (not based on clinical or safety outcomes), the planned phase II dose expansion to 52 evaluable patients at the RP2D did not take place. However, the combination of alisertib plus rituximab and vincristine could be further developed by incorporating an inhibitor of Bruton tyrosine kinase, such as ibrutinib, to overcome the induction of aneuploidy and senescence cells (AASC) during therapy with alisertib (46). Indeed, preclinical studies in double-hit and double-expressor DLBCL have demonstrated that triple therapy with alisertib plus ibrutinib plus rituximab is synergistic and can inhibit AASCs induced by AAK inhibition, resulting in inhibition of proliferation and enhanced apoptosis (46).…”