A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma
<b>Background/Objectives</b>: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). <b>Methods and Results</b>: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets. <b>Conclusions</b>: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.
Authors
- Ritu Pandey
- Baskaran Subramani (ORCID: https://orcid.org/0000-0001-6966-3484)
- Patrick Conway (ORCID: https://orcid.org/0000-0003-2835-5834)
- Aisha Al‐Khinji (ORCID: https://orcid.org/0000-0002-5253-1845)
- Kun Zhang (ORCID: https://orcid.org/0009-0003-3300-5430)
- Daruka Mahadevan
Institutions
- University of Arizona (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Arizona Cancer Center
- Mays Cancer Center at UT Health San Antonio (US)
- The University of Texas at San Antonio (US)
Publication Details
- Journal
- Cancers
- Published
- 2024-12-21
- DOI
- https://doi.org/10.3390/cancers16244257
- Citations
- 1
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.44
Funders
- Health Science Center, University of Tennessee