A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma

Baskaran Subramani; Patrick J. Conway; Aisha Al-Khinji; Kun Zhang; Ritu Pandey; Daruka Mahadevan

doi:10.3390/cancers16244257

A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma

Baskaran Subramani, Patrick J. Conway, Aisha Al-Khinji, Kun Zhang, Ritu Pandey, Daruka Mahadevan

Research output: Contribution to journal › Article › peer-review

Abstract

Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: 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. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.

Original language	English (US)
Article number	4257
Journal	Cancers
Volume	16
Issue number	24
DOIs	https://doi.org/10.3390/cancers16244257
State	Published - Dec 2024

Keywords

Aurora-A
Bruton tyrosine kinase
mantle cell lymphoma
rituximab

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3390/cancers16244257

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title = "A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma",

abstract = "Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: 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. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.",

keywords = "Aurora-A, Bruton tyrosine kinase, mantle cell lymphoma, rituximab",

author = "Baskaran Subramani and Conway, {Patrick J.} and Aisha Al-Khinji and Kun Zhang and Ritu Pandey and Daruka Mahadevan",

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year = "2024",

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doi = "10.3390/cancers16244257",

language = "English (US)",

volume = "16",

journal = "Cancers",

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T1 - A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma

AU - Subramani, Baskaran

AU - Conway, Patrick J.

AU - Al-Khinji, Aisha

AU - Zhang, Kun

AU - Pandey, Ritu

AU - Mahadevan, Daruka

PY - 2024/12

Y1 - 2024/12

N2 - Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: 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. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.

AB - Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: 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. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.

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KW - Bruton tyrosine kinase

KW - mantle cell lymphoma

KW - rituximab

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A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma

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