CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With MYC and BCL2 Rearrangements.

High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.

CS2164 suppresses acute myeloid leukemia cell growth via inhibiting VEGFR2 signaling in preclinical models.

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and resistance to conventional chemotherapy remains one of the greatest challenges in treating the disease. Extensive data have demonstrated that angiogenesis is associated with AML progression and chemotherapy resistance. Thus, targeting angiogenesis may be a promising approach for AML treatment. In this study, we investigated the effectiveness of CS2164 (named as Chiauranib), a novel receptor tyrosine kinase inhibitor, in AML cells. Our results illustrated that CS2164 significantly suppressed cell proliferation and abolished clonogenicity in AML cells in a dose- and time-dependent manner. Meanwhile, CS2164 markedly induced apoptosis of AML cell lines and primary AML cells from 42 adult patients. Furthermore, we found that CS2164 has a comprehensive activity against AML irrespective of disease status and genetic mutations. Also, CS2164 suppressed AML growth in xenograft models in vivo. Mechanistically, CS2164-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including Src/Fyn/p38 and Erk/MEK. In conclusion, our study indicates that CS2164 exerts anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 pathway, supporting a potential role for CS2164 in the treatment of AML.

CS2164 exerts an antitumor effect against human Non-Hodgkin's lymphomas in vitro and in vivo.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders. Mounting studies have suggested an involvement of angiogenesis signaling in NHLs progression and resistance to treatment. In this study, we investigated the cytotoxicity of CS2164, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 and Aurora B in NHL cells. By in vitro culture system and in vivo xenograft model, we found that CS2164 significantly inhibited cell growth and abolished clonogenicity in NHL cells in a dose- and time-dependent manner. Meanwhile, CS2164 significantly induced NHL cells apoptosis and cell cycle arrest in G0/G1 phase. Moreover, CS2164 suppressed NHL cells growth and progression in an in vivo xenograft model. Mechanistically, CS2164-induced cytotoxicity was closely associated with inhibition of VEGFR2 and Aurora B as well as their downstream signaling cascades, including P38, ERK and H3 pathways. In conclusion, CS2164 exerts its cytotoxic effect via inhibition of proliferation and induction of apoptosis by modulating VEGFR2 and Aurora B signaling pathway, supporting a potential role for CS2164 in the treatment of NHLs.